Hepatitis c virus sub-genomic replicons

ABSTRACT

The present invention relates generally to the construction of sub-genomic HCV replicon systems that may provide the foundation for generating HCV replicons of all six major genotypes and subtypes to facilitate screening, testing, and evaluating anti-infective agents for HCV disease(s).

TECHNICAL FIELD OF THE INVENTION

The present invention relates generally to the construction ofsub-genomic HCV replicon systems that may provide the foundation forgenerating HCV replicons of all six major genotypes and subtypes tofacilitate screening, testing, and evaluating anti-infective agents forHCV disease(s).

BACKGROUND OF THE INVENTION

In the U.S., an estimated 4.5 million Americans are chronically infectedwith hepatitis C virus (HCV). Although only 30% of acute infections aresymptomatic, greater than 85% of infected individuals develop chronic,persistent infection. Treatment costs for HCV infection have beenestimated at $5.46 billion for the U.S. in 1997. Worldwide, over 200million people are estimated to be infected chronically. HCV infectionis responsible for 40-60% of all chronic liver disease and 30% of allliver transplants. The CDC estimates that the number of deaths due toHCV will minimally increase to 38,000/yr. by the year 2010.

Due to the high degree of variability in the viral surface antigens,existence of multiple viral genotypes, and demonstrated specificity ofimmunity, the development of a successful vaccine in the near future isunlikely. Alpha-interferon, alone or in combination with ribavirin, hasbeen widely used since its approval for treatment of chronic HCVinfection. However, adverse side effects are commonly associated withthis treatment: flu-like symptoms, leukopenia, thrombocytopenia, anddepression from interferon, as well as hemolytic anemia induced byribavirin (Lindsay, 1997). This therapy remains less effective againstinfections caused by HCV genotype 1, which constitutes ˜75% of all HCVinfections in the developed markets, compared to infections caused bythe other five major HCV genotypes. Unfortunately, only ˜50-80% ofpatients respond to this treatment, measured by a reduction in serum HCVRNA levels and normalization of liver enzymes. Of those patientstreated, 50-70% relapse within six months of cessation of treatment.Recently with the introduction of pegylated interferon, both initial andsustained response rates have improved substantially, and combinationtreatment of Peg-EFN with ribavirin constitutes the gold standard fortherapy. However, side effects associated with the combination therapyand the impaired response in patients with genotype 1 presentopportunities for improvement in disease management.

First identified by molecular cloning in 1989 (Choo et al, 1989), HCV isnow widely accepted as the most common causative agent ofpost-transfusion non-A, non-B hepatitis (NANBH) (Kuo et al., 1989). Dueto HCV's genome structure and sequence homology, this virus was assignedas a new genus in the Flaviviridae family. Like the other members of theFlaviviridae, such as flaviviruses (e.g., yellow fever virus and Denguevirus types 14) and pestiviruses (e.g., bovine viral diarrhea virus,border disease virus, and classic swine fever virus (Choo et al., 1989;Miller and Purcell, 1990)), HCV is an enveloped virus containing asingle strand RNA molecule of positive polarity. The HCV genome isapproximately 9.6 kilobases (kb) with a long, highly conserved,non-capped 5′ non-translated region (NTR) of approximately 340 baseswhich functions as an internal ribosome entry site (IRES) (Wang andSiddiqui, 1995). This element is followed by a region which encodes asingle long open reading frame (ORF) encoding a polypeptide of ˜3000amino acids comprising both the structural and nonstructural viralproteins.

Upon entry of the RNA into the cytoplasm of the cell, it is directlytranslated into a polypeptide of ˜3000 amino acids comprising both thestructural and nonstructural viral proteins. This large polypeptide issubsequently processed into the individual structural and nonstructuralproteins by a combination of host and virally-encoded proteinases(Kolykhalov et al., 1996). Following the termination codon at the end ofthe long ORF, there is a 3′ NTR which roughly consists of three regions:an ˜40 base region which is poorly conserved among various genotypes, avariable length poly (U)/polypyrimidine tract, and a highly conserved 98base element also called the “3′ X-tail” (Kolykhalov et al, 1996; Tanakaet al, 1995; Tanaka et al, 1996; Yamada et al., 1996). The 3′ NTR ispredicted to form a stable secondary structure that is essential for HCVgrowth in chimps and is believed to function in the initiation andregulation of viral RNA replication.

To study the biology of HCV and to screen for compounds that inhibit thevirus replication, a cell-based system to grow the virus is essential.Recently, cell-based replicon systems for HCV were developed, in whichthe nonstructural proteins stably replicate sub genomic viral RNA inHuh-7 cells (Lohmann et al., Science 285:110 (1999) and Blight et al.,Science 290:1972 (2000)). In the absence of a purified, functional HCVreplicase consisting of viral non-structural and host proteins, ourunderstanding of Flaviviridae RNA synthesis comes from studies usingactive recombinant RNA-dependent RNA polymerase (RdRp) and validation ofthese studies in the HCV replicon system. Novel chemical entities, whichinterfere with HCV RNA synthesis, are identified by screening compoundbanks for inhibition of recombinant HCV polymerase in biochemicalassays. However, biochemical inhibition against this purified enzymedoes not necessarily translate into replicon cell-based inhibition sincein the latter system the polymerase exists within a replicase complex,associated with other viral and cellular polypeptides in appropriatestoichiometry. Moreover, in the absence of a robust small animal modelfor HCV infection, the replicon system more accurately represents anactive infection than other in vitro systems.

However, despite the existence of infectious cDNA clones and manyattempts to cultivate the virus in established cell lines inlaboratories, efficient in vitro replication of the HCV virus has notbeen established prior to the present invention. A sub-genomic HCVreplication system was successful in the human hepatoma cell line Huh-7after electroporation of a particular genotype 1b, BB7 strain, RNAreplicon containing a neo resistance marker (Lohmann et al., Science285:110, 1999). The replicon is a di-cistronic construct containing the5′ untranslated region of HCV (5′ NTR), a neomycin resistance gene(neo), the non-structural genes NS3 to NS5 and the 3′ non-translatedregion of HCV (3′ NTR). Translation of neo and NS3 to NS5 genes ismediated by HCV 5′ NTR and EMCV IRES, respectively. Improved replicons,containing high-levels of viral sub-genoric RNA copies were obtained byselection for adapted mutations in Huh-7 cells (Blight, K. J. et al.2000; Lohmann et al. 2001; Guo et al. 2001).

Huh-7 cell-based replicon systems for HCV were constructed so that thenon-structural proteins replicate sub-genomic viral RNA. One significantlimitation of the available replicon systems is the inability of othergenotypic derivatives, beyond that of two specific strains of genotype1b (HCV-N and HCV-BB7), to replicate in Huh-7 cells. The generation offunctional replicons for HCV genotypes 1 to 6 would be invaluable inefficiently developing antiviral agents, and solves a longstandingproblem.

SUMMARY OF THE INVENTION

In view of the aforementioned deficiencies associated with prior art HCVreplicons, cell culture systems for the analysis of HCV replication, andthe development of therapeutic compositions therefor, it is evident thatthere exists a need in the art for identification of chimericsub-genomic replicons of HCV which can be incorporated into a cellcapable of replicating RNA transcripts. These transcripts can then beused as target sequences for the production of attenuated HCV forvaccines, and targets for therapeutic compositions.

In accordance with the present invention, nucleotide sequences derivedfrom various functional chimeric HCV replicons are provided herein.Through molecular cloning and tissue culture technologies as well asdetailed analysis of the literature, the present invention describes thesuccessful generation of stable cell lines expressing and replicatingfunctional replicons, containing sequences from HCV genotype 1a (strainH77) or genotype 1b (strain J4) within the prototype 1b repliconbackbone from HCV strain BB7. The methodology used to create thesefunctional replicons described herein which express (1) genotype 1asequences or (2) genotype 1b sequences from other strains not previouslyshown to be functional in such systems provides the foundation andknow-how for generating HCV replicons of all six major genotypes andsubtypes to facilitate screening, testing, and evaluating anti-infectiveagents for HCV disease(s).

One embodiment of the invention is a sub-genomic viral replicon thatcontains a nucleic acid construct encoding chimeric HCV nonstructuralproteins and a complete NS5B polymerase. A further embodiment providesan NS5B encoding sequence linked in cis to a 3′UTR sequence of an HCVstrain, preferably the same HCV strain.

In another embodiment, a chimeric replicon includes the nonstructuralproteins NS3, NS4A, NS4B, NS5A, and NS5B. In a further embodiment of theinvention, a chimeric replicon comprises an NS3 nucleotide sequence thatencodes about the first 75 contiguous N-terminal amino acids of NS3 ofgenotype 1b. A preferred embodiment of the invention is a chimericreplicon that contains the NS3 encoding nucleotide sequence of agenotype 1b, BB7 strain. The nucleotide sequence that encodes the first75 contiguous N-terminal amino acids of HCV type 1b, strain BB7 isATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCAC(SEQ ID NO: 1)AGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATG

In still another embodiment of the invention, a chimeric repliconcomprises an NS3 from any of the other six major HCV genotypes andsubtypes wherein a particular NS3 has its N-terminal first 225nucleotides replaced by the N-terminal first 225 nucleotides of NS3 ofthe genotype 1b, BB7 strain. For example, a preferred embodiment of theinvention comprises a replicon wherein the N-terminal sequence of NS3genotype 1b, BB7 strain, replaces the corresponding N-terminal sequenceof NS3, genotype 1a. In addition, another embodiment is provided whereina NS3 sequence is from the genotype 1a, H77 strain. In yet a furtherembodiment, an NS3 sequence is from the genotype 1b, J4 strain.

Another embodiment of the invention is a sub-genomic viral replicon thatcomprises a nucleic acid construct encoding chimeric HCV nonstructuralproteins, and at least the C-terminal end of a strain specific NS5Bpolymerase gene linked in cis to a 3′UTR sequence from said strain.Specifically, a preferred embodiment of the invention is a chimericreplicon wherein the NS5B comprises sequence from both a BB7 strain anda J4 strain, see FIG. 2(b), the J4M/S construct. The C-terminal portionof BB7's NS5B is linked in cis to a 3′UTR sequence of a BB7 strain.However, the N-terminal portion of NS5B is sequence from the J4 strain.In an embodiment of the invention, there is provided a construct whereinless than the complete NS5B from a single HCV strain is used becauseboth BB7 and J4 are of the same subtype, 1b.

In another embodiment of the invention, a replicating HCV sub-genomicreplicon comprises SEQ ID NO:2, SEQ ID NO:6, SEQ ID NO:7, or SEQ IDNO:8.

A further embodiment of the invention includes a method for introducinga HCV replicon into a cell. The method produces a cell comprising areplicating chimeric HCV sub-genomic viral replicon. A preferredembodiment a cell of the invention comprising a HCV sub-genomic repliconfurther comprising all of the non-structural HCV genes and none of thestructural HCV genes.

A further embodiment of the invention is a method of screening forcompounds that modulate viral replication comprising the steps ofadministering a test compound to a cell comprising a replicatingchimeric HCV sub-genomic viral replicon and determining whether saidtest compound modulates replication of said subgenomic replicon.

Another embodiment of the invention includes a method of screening forcompounds that inhibit viral replication comprising the steps ofadministering a test compound to a cell comprising a replicatingchimeric HCV sub-genoric viral replicon and determining whether saidtest compound inhibits replication of said chimeric sub-genoric viralreplicon.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a comparative sequence alignment of 3′UTR coding regionfrom genotype 1a and 1b strains.

FIG. 2 schematically depicts the novel replicon constructs in comparisonwith the prototype pHCVrep1b(BB7). Replicon pHCVrep1b(BB7) containsnoncoding sequences in thin lines and protein coding sequences in boxes(neo=G418 resistance gene; NS3 to NS5B=nonstructrual protein genes). Thearrow on top of the figure shows the translation start codon AUG and theNS5A adaptive mutation Serine 1179 Isoleucine. The arrows below theFigure indicate the relevant restriction sites in the DNA plasmid usedfor sub-cloning. B, Bsr GI; RI, Eco RI; M, Mfe I. Stripped boxesindicate DNA sequences derived from pCVJ4, Shaded boxes indicatesequences derived from pCVH77. 5′ and 3′ NTR sequences are indicatedwhile the nucleotide changes in 3′NTR are pointed out by the nucleotideunder the 3′NTR. Replication capability was indicated by + and − signsat the left of the figure.

FIG. 3 depicts Huh-7 cell colony formation. Colonies formed afterselection in G418 containing media for over four weeks were stained with5% crystal violet in methanol and photographed.

FIG. 4 depicts a Western blot of stable replicon cells expressing NS5A.Total replicon cell protein was separated on 8% SDS-PAGE, transferred tonitrocellulose paper and probed with anti-NS5A serum. Replicon cell Aserves as positive control, while Huh-7 cell as negative control. Themolecular weight is indicated.

FIG. 5 illustrates an analysis of replicon genomic DNA by PCR. GenomicDNA from each replicon cell line was purified and used as substrates inPCR reactions to amplify either GDAPH or Neo resistance gene. While inboth H77 1A (F1) and J4 M/S cells, DNA for GAPDH was amplified,indicating that the good quality of genomic DNA, no Neo DNA wasdetected. For positive control of the reaction, amplification of neo DNAwas from a neo plasmid DNA.

FIG. 6 illustrates a genome copy number determination by TaqMananalysis.

DETAILED DESCRIPTION OF THE INVENTION

Through molecular cloning and tissue culture technologies, the presentinvention produced functionally stable cell lines expressing andreplicating replicon RNA consisting of sequences from HCV genotype 1a,strain H77, within the prototype genotype 1b replicon, strain BB7,backbone. The type 1a replicon system is characterized in detail anddiscussed herein.

Specifically, expression of HCV viral proteins, NS3, NS5A, and NS5B,were detected by Western blot and in situ immunofluoresence analysis.Positive- and negative-strand replicon RNA was quantified by TaqMan andfull length RNA was confirmed by northern blot analysis. Susceptibilityto interferon and antiviral agents was shown to be similar whencomparing with the type 1b replicon system. Lastly, cDNA was generatedfrom replicon cell RNA by RT-PCR, and as many as 18 clones weresequenced to identify adaptive mutation(s) not present in the parentalH77 sequence. The non-structural genes NS3, NS5A, and NS5B containedfour mutations. While the two mutations in NS3 were found in all clones,the mutations in NS5A and NS5B were always present in a same subset ofclones.

Huh-7 cell-based replicon systems for HCV were developed, in which thenonstructural proteins stably replicate sub-genomic viral RNA. (Lohmannet al., Science 285:110 (1999) and Blight et al., Science 290:1972(2000)). Although two specific strains of genotype 1b, (HCV-N andHCV-BB7), have been confirmed to be functional in Huh-7 cells, it is notclear why other strains of genotype 1b are unable to replicate. Thepresent invention is based, in part, on understanding the interplay ofhow certain adaptive mutations confer competence in Huh-7 cells for oneviral strain, yet altogether different mutations are critical for adifferent viral strain would facilitate the creation of functionalreplicons for HCV genotypes 1 to 6.

These functional chimeric replicons are valuable tools that enable oneskilled in the art to adapt known replicon systems to other HCVgenotypes, such as HCV type 1a strain H77 (Yanagi, M. et. al. 1997) andHCV type 1b strain HC-J4 (Yanagi, M. et al. 1998), which have not beenreported as successful. The reported cDNA for genotype 1b, strain J4,was constructed using the 5′ and 3′ untranslated regions of a genotype1a strain (Yanagi, M. et al. 1998). The infectivity of three full-lengthcDNA clones was tested by direct injection of RNA transcripts into theliver of a chimpanzee and only one of the three clones was found to beinfectious. The infectious clone coding region contained three aminoacid changes from the parental J4 strain. Moreover, heterogeneity of the3′UTR was examined and several changes compared to the parental genotype1a 3′UTR were identified (nt 9407, 9399, poly U-UC region varied inlength and complexity, and several point mutations in the conservedregion of the 3′UTR. Although not mentioned by these authors, it isprovided by this invention that these in vivo-selected changes indicatethat the generation of functional HCV genomes requires a specific NS5Bpolymerase sequence (e.g., J4 strain polymerase sequence) to be linkedin cis to its cognate 3′UTR sequences (e.g., J4 strain 3′UTR sequence).Replication of negative strand by NS5B initiates at the 3′UTR, andcoordination of specific sequences in these two regions directsfunction. The present invention further provides generation of chimericreplicons containing genotype 1b sequence from the J4 strain that arenonfunctional when paired with 3′UTR sequences from genotype 1a strains.The invention thus explains the lack of reported J4 strain replicons todate, but in no way is the invention limited by this hypothesis.

The present invention provides certain sub-genomic replicon constructs.A replicon comprising both the polyprotein coding sequences and 3′UTRsequences from a genotype 1a, strain H77, cDNA is functional, based onthe in cis pairing of NS5B and 3′UTR from same strain. Moreover,functional replicons are provided wherein all polyprotein codingsequences except NS5B were replaced by sequences of genotype 1b, strainJ4, while leaving NS5B and 3′UTR sequences intact from genotype 1bsequences reported in the BB7 1b functional replicon. Lastly, based onthe 3′UTR sequences in FIG. 1, replicons containing solely J4 strainsequences function if the genotype 1a 3′UTR from the infectious cDNA isreplaced with the 3′UTR from genotype 1b, strain J4. Data confirmingthis result is provided elsewhere herein.

In addition, the hybrid clones of the present invention retained aportion of the 5′ sequence of the non-structural gene NS3, genotype 1b,of the BB7 replicon. The first 225 nucleotides of genotype 1b replacedthe corresponding 5′ end of the non-structural gene NS3 of eithergenotype 1a or genotype 1b, J4 strain.

The present invention discloses a panel of constructed BB7 strainchimeras, among others. These chimeras comprise sequences from theinfectious strains J4, type 1b or H77, type 1a. The J4/BB7 chimericreplicons comprising coding sequence for NS3, NS4A, NS4B, NS5A, and 132amino acids of NS5B from J4 and the remainder of the replicon from BB7efficiently replicated in Huh-7 cells. However, replacement of BB7 NS5Band 3′NTR with J4 strain sequences failed to result in stable cell linegeneration, although transient replication was not ruled out. TheH77/BB7 chimeric replicons containing NS3, NS4A, and NS4B sequences fromH77 supported replication in Huh-7 cells, although replacement of BB7NS5A and the N-terminal 132 amino acids of NS5B with H77 sequencesrendered this replicon deficient. Lastly, replacing a portion of BB7NS5B and 3′NTR elements with H77 sequences also did not confer stablereplication in Huh-7 cells. Surprisingly, a chimeric replicon wherebythe entire BB7 NS5B was replaced with H77 sequences resulted inefficient colony formation and stable replication in Huh-7 cells.Adaptive mutations were found in the H77 NS5B region of this replicon.Such replicons could be used for cell-based testing of antiviral agents,among other uses, against NS3 and NS5B from strains J4 and H77.

In the present invention, certain chimeric replicon constructs weregenerated from pHCVrep1b(BB7) with sequences substituted with eithertype 1aHCV H77 sequence or by HCV type 1b J4 strain sequence. Ratherthan trying to replace only the NS5B coding region, as other groups haveattempted but failed to achieve, the present invention was based, inpart, on the methodical replacement of sections of the pHCVrep1b(BB7)nonstructural genes with 1a or J4 1b sequences. Replicon RNA prepared invitro for the majority of these chimeras (BB7-F1/F2, BB7-F3, BB7-F3(C),J4B/R1, J4 B/R1 (C), J4 replicon, J4 replicon (c), and BB7/J4NS5B, seeFIG. 2) failed to yield stable cell lines after transfection into Huh-7cells. However, surprisingly, constructs BB7-F1, BB7/H77NS5B, HCV1areplicon and J4 MIS were able to stably replicate and confer resistanceto G418. The methods for constructing these replicons are describedherein.

Evaluation of the functional replicon constructs demonstrated certainfindings that are, in certain embodiments, important for chimericreplicon generation of multiple genotypes and subtypes: (1) A portion ofNS5B, starting at residue 133, from strain BB7 genotype 1b can conferreplication, albeit at low levels and (2) the 3′NTR sequences from BB7can confer replication of the replicon, albeit also at low levels. Boththe 3′NTR and a portion of residues from NS5B are, in certainembodiments, important components which together control replication ofthe sub-genomic RNA in Huh-7 cells. This finding indicates thatinclusion of nonstructural gene sequences from other strains andgenotypes results in a functional replicon if sequences for NS5B and3′NTR region are from the same strain, for example BB7.

The invention further provides that other NS5B sequences can replace BB7NS5B sequence, if paired with their cognate 3′NTR sequence elements.Moreover, certain sequence changes in the BB7 3′NTR, compared to changesin the J4 3′NTR indicate the basis of NS5B:3′NTR interaction, andthereby confer stable replication in Huh-7 cells. FIG. 1 shows analignment of 3′NTR sequences from different strains.

Various definitions are used throughout this document. Most words havethe meaning that would be attributed to those words by one skilled inthe art. Words specifically defined either below or elsewhere in thisdocument have the meaning provided in the context of the presentinvention as a whole and as typically understood by those skilled in theart.

As used herein, the term ♭replicon” refers to a viral nucleic acid thatis capable of directing the generation of copies of itself. As usedherein, the term “replicon” includes RNA as well as DNA, and hybridsthereof. For example, double-stranded DNA versions of HCV genomes can beused to generate a single-stranded RNA transcript that constitutes anHCV replicon. Generally, a viral replicon contains the complete genomeof the virus. “Sub-genomic replicon,” as used herein, refers to a viralnucleic acid that contains something less than the full complement ofgenes and other features of the viral genome, yet is still capable ofdirecting the generation of copies of itself. For example, thesub-genomic replicons of HCV described below contain most of the genesfor the non-structural proteins of the virus, but are missing most ofthe genes coding for the structural proteins. Sub-genomic replicons arecapable of directing the expression of all of the viral genes necessaryfor the replication of the viral sub-genome, replication of thesub-genomic replicon, without the production of viral particles.

An HCV sub-genomic replicon, may be derived from any of the various HCVstrains and isolates, such as, but not limited to, any of the isolatesfrom genotypes 1, 2, 3, 4, 5 or 6 of HCV. Moreover, the various genesincluded in the sub-genomic replicon can be derived from differentstrains. The complete genotypes of many of these strains are known. See,e.g., U.S. Pat. No. 6,150,087 and GenBank Accession Nos. AJ238800 andAJ238799, International Publication Nos. WO 89/04669; WO 90/11089; andWO 90/14436. Moreover, the genes included in the sub-genomic repliconmay be full-length, fragments or variants of the native sequence, solong as the sub-genomic replicon remains capable of expressing the viralgenes necessary for replication thereof, without producing viralparticles. Thus, for example, the genes included in the sub-genomicreplicon may be homologous to the native genes.

The phrase “stably replicating” as used herein in reference to thesub-genomic replicons means the steady, continuous generation of newsub-genomic replicons in the cells into which initial sub-genomicreplicon transcripts are introduced, as well as their progeny cells. Thetransfected cells continue to proliferate, and the sub-genomic repliconscontinue to replicate.

The term “cell” as used herein refers to single cells as well as to thecollection of cells in culture derived from a single progenitor cell,otherwise referred to as cell lines.

As used in this specification and the claims, the singular forms “a,”“an” and “the” include plural references unless the content clearlydictates otherwise. Thus, for example, reference to “a cell” includes amixture of two or more cells.

Many different cell types can be used to practice the invention. In apreferred embodiment of the invention, the cell used is a human livercell. More preferably, the cell is a hepatocellular carcinoma-derivedcell. In a non-limiting example, the cell is Huh-7 (Nakabayashi et al.,1982, Cancer Res., 42:3858-3863; Seki et al., 1999,Hepatogastroenterology, 46:2812-2817). In another non-limiting example,the cell is HepG2 (U.S. Pat. No. 4,393,133). Other cell lines in whichthe invention may be practised include, but are not limited to, mycimmortalized human liver cell lines, and primary cultures of fetalhepatocytes (Sanchez et al., 1995, J. Cell Physiol, 165:398-405).

Another aspect of the invention provides methods of screening forcompounds that modulate replication of viral RNAs either directly orindirectly. Compounds can be screened for their effect on thereplication of sub-genomic viral replicons in the cells of the inventionby treating the cells with test compounds. Compounds that target theviral genes and/or proteins involved in the replication of sub-genomicviral replicons can be identified in screens of the invention where anHCV sub-genomic replicon can stably replicate.

The cells of the present invention can be used to identify compoundsthat inhibit viral RNA replication, and hence, viral replication, or toidentify compounds that enhance viral RNA replication, and hence, viralreplication. In particular, compounds identified as having inhibitoryeffects on the replication of HCV sub-genomic replicons will becandidates for use as drugs in the treatment of HCV infection anddisease. Compounds exhibiting replication-enhancing activities will becandidates for use in the development of further cellular and animalmodel systems of HCV replication.

There are a variety of HCV targets for test compounds, including, butnot limited to, HCV internal ribosomal entry sites, HCV NS3 serineproteinase, NS3 RNA helicase, NS5B RNA dependent RNA polymerase, andother HCV non-structural proteins. For example, compounds may interferewith the process of viral replicon replication by interfering with theviral proteins that are critical to RNA replication, all of which aretranslated off of the transcripts being generated in HCV sub-genomicreplicon-containing cells of the present invention.

When a selectable drug resistance marker is included in the sub-genomicreplicon, compounds can be assessed for their ability to sensitize cellsto the selectable drug, i.e., to render the cells sensitive to the drugthat was used to select them. Test cultures where cells die off areindicative of compounds that interfere with replicon replication,because loss of the drug-selectable replicon renders the cells sensitiveto that particular drug. Where, for example, a neo resistance marker isused in conjunction with the viral sub-genomic replicon, loss of theneo-selectable, sub-genomic replicon will render the cells sensitive toG418.

As used herein, the term “compound” means any identifiable chemical ormolecule, including, but not limited to small molecules, peptides,polypeptides, proteins, sugars, nucleotides, or nucleic acids. Suchcompounds can be natural or synthetic.

As used herein, the term “modulates” in reference to host replicationactivity means results in a change in the amount, quality, or effect ofa particular response or activity. Both increases and decreases in theresponse or activity are included.

As used herein, the term “chimeric” means a molecule of RNA, DNA, orprotein that has resulted from recombination, or has resulted from DNAfrom two sources fused or spliced together.

The invention is further illustrated by way of the following exampleswhich are intended to elucidate the invention. These examples are notintended, nor are they to be construed, as limiting the scope of theinvention. It will be clear that the invention may be practisedotherwise that as particularly described herein. Numerous modificationsand variations of the present invention are possible in view of theteachings herein and, therefore, are within the scope of the invention.

EXAMPLES Example 1 Construction of Replicons Comprising HCV Type 1a H77Sequence

The present invention utilized PCR, in which pCV-H77C DNA was used astemplate to amplify a DNA fragment (F1) which contains NS3, starting atamino acid 76, NS4A, NS4B, and the N terminal of NS5A, ending at aminoacid 148. The primers are designed according to the pCV-H77C DNAsequence with only one nucleotide change in each of the 5′ and 3′primers. A single T to C change in the 5′ primer BG1000 incorporated aBsrGI restriction site while a single T to C change in the 3′ primerBG0002 created an Eco RI restriction site. Neither changes in the DNAsequence caused changes in the encoded amino acid sequences. The PCRproduct was digested with Eco RI and Bsr GI restriction enzymes andcloned into pHCVrep1b(BB7) vector that has been digested with the sameenzymes. The resulting chimeric construct, pBB7-F1 was selected based onthe lack of a Mlu I restriction site in the substituted H77 sequence andconfirmed by DNA sequencing analysis.

PCR was utilized to amplify DNA fragment F2 by using H77 DNA as templateand the primers BG1001 and BG1004. F2 extends from within NS5A (startingat amino acid 149) to NS5B (ending at amino acid 132), encompassing theS1179I adpative mutation. BG1001 is complementary to BG1002 andcontained a single A to G nucletide change and an Eco RI restrictionsite. Similarly, a T to A change was built in BG1004 from the H77sequence to create an Mfe I restriction site. To make the S1179Iadaptive mutation, the 1.3 kb F2 was digested with Eco RI and MfeI andcloned into the corresponding sites in pLitmus 38 and subjected tooligonucleotide-directed mutagenesis with 1aS9484I and 1aS9484I R. Themutagenized fragment was subsequently cloned into pBB7-F1 that has beendigested with Eco RI and Mfe I to produce pBB7-F1/F2.

An additional DNA fragment was amplified from H77 DNA by PCR to generatean F3(c) fragment containing H77 HCV 1a sequence from NS5B, at the endof F2, starting at amino acid 133, to the 3′ end of HCV genome. The 5′primer BG1003 contains an MfeI site and the 3′ primer RB8000 contains aSpe I restriction site followed by a Sca I site. The ScaI site marks theend of the HCV genome in that after Sca I digestion and transcriptionthe authentic RNA 3′ was produced. The RB8000 oligonucleotide has twochanges from H77 in sequence, an A to T change at the −3 position and Ato T change at the −44 position. The changes reflected the DNA sequencein pBB7 and preserved the base-pairing structure of the 3′ X tail(Yanagi, M et al. 1999). F3(c) fragment was digested with Mfe I and SpeI and purified from agose gels. It was ligated into pBB7-F1/F2 vectorthat was digested with Mfe I and Spe I to generate pBB7-F1I/F2/F3(c) orHCV 1A replicon. The F3 (C) fragment was also directly cloned intopHCVrep1b(BB7) to replace the corresponding DNA to make pBB7-F3(c).Similarly, Mfe I-Spe I fragment without the single nucleotide change F3was cloned into pHCVrep1b(BB7) to generate pBB3-F3.

A replicon containing HCV type 1a NS5B, pBB7/H77NS5B, was constructed inmultiple steps. First, a unique Sna BI site was introduced intopHCVrep1b(BB7) at the end of the NS5B gene. To accomplish this, two DNAfragments were amplified by using pHCVrep1b(BB7) as template and theprimer pairs: rb6000 CGTCTGCTGCTCGATGTCCTAC and RB7801 3′ [SEQ ID NO:15]CTCCCCCAACCGATGAACGGGTACGTAAACACTCCAGGCCAATAG; BG1005 [SEQ ID NO: 16]GCACTAGTACTTGATCTGCAGAGAGGC and RB7801 5′ [SEQ ID NO: 17]CTATTGGCCTGGAGTGTTTACGTACCCGTTCATCGGTTGGGGGAG. [SEQ ID NO: 18] RB7801 5′and RB7801 3′ are complementary primers derived from sequences at theend of NS5B. Two nucleotide sequences (underlined sequences) werechanged from the BB7 HCV sequence so that a Sna BI site is created. Thesequence changes do not affect the NS5B sequence since they are 3′ tothe NS5B coding region. By using RB7801 3′ and rb6000, a 1.4 kb NS5Bfragment was generated. By using RB7801 5′ and BG1005, a 220 bp 3′NTRsequence was generated. The two fragments were purified, annealed andthe annealed product used as templates in PCR reactions to generateNS5B-3′NTR fragment. This fragment was digested with Bc1 I and Spe I andthe resulting DNA ligated into pBB7 vector that were digested with thesame restriction enzymes. The resulting plasmid, designated pBB7-SN, wasconfirmed to contain a Sna BI restriction site at the end of NS5B byrestriction digestion and DNA sequencing. The NS5B gene fragment frompBB7-SN DNA was then replaced with other NS5B genes by cloning into theBc1I and Sna BI restriction sites. Replicon RNA transcribed from pBB7-SNcan replicate efficiently when electroporated into Huh-7 cells. Togenerate pBB7/H77NS5B, the HCV type 1a H77 NS5B gene was first amplifiedby using H77 DNA and primers RB7801 3′ and 1A 10501CCTGGACAGGCGCACTGATCACC [SEQ ID NO: 19]. Two nucleotides were changedfrom the type 1a sequence to create a Bcl I site which caused a V to Isubstitution in H77 NS5B. After digestion with Bcl I and Sna BI, the H77NS5B fragment was ligated to pBB7-SN vector prepared by digestion withthe same restriction enzymes. Replacement of BB7 NS5B by H77 NS5B wasconfirmed by the introduction of an Eco RI restriction site. Similarly,pBB7/J4NS5B was constructed by cloning into pBB7-SN PCR fragmentsgenerated by using the primer pairs rb6000 and RB7801 3′ and pCVJ4L6SDNA.

For synthesis of all other hybrid J4 replicons, multiple cloning stepswere used. First, pCVJ4L6S DNA was digested with BsrG I and Mfe I andthe 4.3 kb DNA fragment encoding NS3 (from amino acid 75), NS4A, 4B,NS5A, and the N terminal 132 amino acids of NS5B was purified fromagrose gels. The fragment was ligated with pHCVrep1b(BB7) vectordigested with the same restriction enzymes to generate pBB7-J4. pBB7-J4was distinguished from pHCVrep1b(BB7) by Hpa I digestion. pBB7-J4 hasonly one Hpal site while pHCVrep I b(BB7) has two. To put together theJ4 replicon, primers J4-10861: GAGGACTTGCTGGAAGACACTG [SEQ ID NO:20] andBB7980: CAGGAGTACTTGATCTGCAGAGAGGC [SEQ ID NO:21] was used in PCRreactions to amplify the J4 DNA fragment 3′ to the Mfe I site. The DNAwas digested with Mfe I and Sca I restriction enzymes and cloned intopBB7-J4 to create pJ4/BB7. To add the NS5A adaptation mutation S11791 inpHCVrep1b(BB7) to pJ4/BB7, the 1.3 kb Eco RI to Mfe I DNA fragmentencoding part of NS5A surrounding the S11791 was subcloned into pLitmus38. The resulting plasmid was subjected to oligonucleotide-directedmutagenesis to introduce the S11791 change by using the oligos J4-9841Tand J49841TR. The mutagenized Eco RI-Mfe I fragment was used to replacethe wildtype fragment in pJ4/BB7 to generate pJ4replicon. Regionscontaining the mutation in pJ4replicon were sequenced and both the J4sequences and the S1179I mutation were confirmed. The pJ4replicon DNAalso has the single nucleotide change (A to T at −40 position) in its3′NTR X tail. This was fixed by first generating a PCR fragment by usingthe primer pairs BB8000 and J4-10861 and then replace the Mfe I-Spe Ifragment in pJ4 replicon with the PCR fragment. The replicon with thecorrected 3′ X tail is designated pJ4 replicon(c). The Mfe I-Spe I andBsrGI-Eco RI fragments from pHCVrep1b(BB7) were used to replace thecorresponding sequence in pJ4 replicon(c) to make pJ4M/S and pJ4 B/R1(c), respectively. The BsrGI-EcoRI fragment from pHCVrep1b(BB7) was alsoused on pJ4replicon to make pJ4 B/RI, which differs from pJ4B/RI(c) by amutation in the 3′ X tail.

RNA transcribed from the above replicon DNA was electroporated intoHuh-7 cells according to the procedures in the examples. G418 resistantcells were obtained by incubating the cells in G418-containing media.Once the cells were amplified, total cellular protein was separated onSDS-PAGE and probed by NS5A serum to assess whether HCV proteins wereexpressed. As predicted, all three replicon cell lines expressed NS5A asshown on figure. Genomic DNA and RNA were also isolated from eachreplicon cell lines. PCR reactions on genomic DNA were carried out toassess the possibility that the G418 resistance was due to expression ofthe phosphatransferase from integrated neo resistant gene into the Huh-7cell genome. As shown in FIG. 4, while the PCR reaction amplified afragment of neo DNA when using genomic DNA from a neo resistant cellline was used as substrate, no neo specific product was amplified fromequivalent amount of genomic DNA from pJ4 M/S, pBB7-F1 andpHCVrep1b(BB7). However, when the same genomic DNA was used to amplify aGAPDH DNA fragment, the expected sized DNA was amplified readily,suggesting that the genomic DNA is of good quality. Therefore, the dateindicate that it is unlikely that the resistance is due to integrationof residue DNA in our RNA preparation into the genome of Huh-7 cells.

Next, replicon RNA was quantified by TaqMan. Real-time PCR was conductedwith primers and probes in the neo gene on total RNA isolated from thereplicon cells and on standard neo containing DNA. Copy numbers of thereplicon were calculated based on standard curve generated from knownamount of in vitro transcribed RNA. J4 M/S contained about 147copies/cell, BB7-F1 contained 57 copies/cell, HCV 1a replicon has 165copies/cell, BB7/H77NS5B has 29 copies/cell. For a positive control, HCVBB7 replicon that has 1500 copies/cell while Huh-7 cells served asnegative controls.

Example 2 Cells, Media, DNA Cloning

Huh-7 cell lines were cultured in Dulbecco's Modified Eagle Media (DMEM)(Invitrogen #11965-084) containing, 10% fetal calf serum (FCS) (JRHBiosciences #12103-78P), 1% penicillin-streptomycin (P-S) (Invitrogen#15140-122), 1% non-essential amino acids (NEs) (Invitrogen #11140-050),and 1 mg/ml Geneticin (herein “G418”) (Invitrogen 11811-023).

Example 3 Construction of Hybrid H77 Replicons

PCR was carried out to amplify a DNA fragment (F1) which contains NS3(from amino acid 76), NS4A, 4B and the N terminal of NS5A (148 aminoacids) by using HCV-H type 1a DNA as substrate. The 100 ul reactioncontains 1× pfu PCR buffer (Strategene), 0.25 uM BG1000, 0.25 uM BG1002primers, 10 ng HCV type 1A DNA, 2 units turbo pfu DNA polymerase. ThePCR conditions were set at 95 C for 30 seconds, 60 C for 30 seconds, 72Cfor 3 minutes for 25 cycles. The DNA product was purified from an agrosegel by Qiagen Quick gel kit, digested with BsrGI and EcoRI restrictionenzymes. After purification, the DNA fragment was ligated intopHCVrep1b(BB7) vector DNA that was previously digested with BsrGI andEcoRI enzymes. The recombinant plamids were distinguished frombackground pHCVrep1b(BB7) plamids by DNA digestion with Mlu I.pHCVrep1b(BB7) has a Mlu I site in the substituted region, whilerecombinant pBB7 F1 lacks the Mlu I site. pH77 F1 DNA was prepared andsequence confirmed to contain type 1A sequences.

PCR reactions were carried out to amplify another DNA fragment (F2) byusing H77 DNA as template and the primers BG1001 and BG1004. F2 extendsfrom within NS5A to the 132 amino acid of NS5B, encompassing the S1179Iadaptive mutation. BG1000 is complementary to BG 1002, thus containing asingle nucleotide change, A to G, and an Eco RI restriction site.Similarly, a T to A change was built in BG1004 from the H77 sequence tocreate a Mfe I restriction site. The 1.3 kb PCR product was digestedwith Eco RI and MfeI and cloned into the corresponding sites inpLitmus38 and subjected to oligonucleotide-directed mutagenesis with theoligos J4-9841T and J49841TR. The mutagenized fragment was subsequentlycloned into pBB7-F1 that has been digested with Eco RI and Mfe I toproduce pBB7-F1/F2.

Another DNA fragment was amplified from H77 DNA by PCR to generate aF3(c) fragment which contains H77 HCV 1A sequence from the end of F2 tothe 3′ end of HCV genome. The primers are BG1003, which was designed tocontain an Eco RI site and RB8000, which contain a Spe I restrictionsite right next to a Sca I site. The ScaI site marks the end of the HCVgenome in that after Sca I digestion and transcription the authentic RNA3′ was produced. The oligonucleotide has two changes from H77 insequence, an A to T change at the minus 3 position and T to A change atthe minus 44 position. The changes reflected the DNA sequence in pBB7and preserved the base-pairing structure of the 3′ X tail (Yanagi, M etal. 1999). F3(c) fragment was digested with Mfe I and Spe I and purifiedfrom agarose gel. Then ligated into pBB7-F1/F2 vector that was digestedwith Mfe I and Spe I to generate pBB7-F1/F2/F3(c) or HCV 1A replicon.The F3(c) fragment was also ligated into pBB7 vector to generatepBB7-F3(c). Another construct was generated by cloning an F3 fragmentcontaining the mismatch in the 98 nt x-tail. The −44 position was leftto have the T, but the −3 position was changed to T to create the Sca Isite. This construct is designated pBB7-F3. TABLE 1 The restrictionsites and there positions as used in the construction of the replicons.BsrGI nt 2024 (NS3 aa#75) Eco RI nt 5083 (NS5A aa#148) Mfe I nt 6383(NS5B aa#132) Sna BI nt 7764 (3′NTR)

TABLE 2 Summary of nucleotide and amino acid changes in HCV 1a repliconand BB7/H77NS5. Changes in HCV 1a replicon: Position Nucleotide ChangeAmino acid change I. BB7 adaptive mutation: 5336 G to T NS5A S232I II.HCV 1a adaptive muation: 2797 T to C NS3 S332P 3550 A to G NS3 K583E4682 A to T NS5A E14V 6520 G to A NS5B V179I 6936 C to A none 7356 G toA none III. changes made during cloning: 2028 T to C (create BsrGI site)none 5088 T to C (create Eco RI site) none 6387 A to T (create Mfe Isite) none Mutations in BB7/H77NS5B: 6012 C to G NS5B V11I 6013 G to ANS5B V11I 7024 G to T NS5B A348S

Example 4 Construction of Hybrid J4 Replicons

pHCV J4 DNA was digested with BsrG I and Mfe I and the 4.3 kb DNAfragment containing type 1B NS3 (from amino acid 75), NS4a, 4B, NS5A,and the N terminal 132 amino acids of NS5B was purified from agrosegels. The fragment was cloned into pHCVrep1b(BB7) vector DNA that wasdigested previously with the same restriction enzyme to generatepJ4M/S*. To add the NS5A adaptation mutation S11791 in pHCVrep1b(BB7) topJ4 M/S*, a 1.3 kb Eco RI to Mfe I DNA fragment from pHCVrep1b(BB7) wassubcloned into pLitmus 38 and subjected to oligonucleotide-directedmutagenesis. The oligonucleotides J4-9841T:CTTTAGCCAGCTCATCAGCTATCCAGTTGTCTGCGCCTTC [SEQ ID NO:22] andJ49841TR:GAAGGCGCAGACAACTGGATAGCTGATGAGCTGGCTAAAC [SEQ ID NO:23] wereused in PCR reactions according to the manufacturer's directions. Themutagenized Eco RI-MfeI fragment was then cloned into pJ4M/S* togenerate pJ4M/S. DNA of pJ4M/S was sequenced to confirm both the J4sequences and the S1179I mutation.

Example 5 In Vitro Transcription and DNase Digest of Replicon RNA

Replicon plasmid DNA was linearized with Sca I (New England Biolabs)using 1 U/1□g DNA for 1 hour at 37° C. The linearization of the plasmidgenerates the authentic 3′ end of the HCV 3′NTR and provides thetemplate to generate the appropriate RNA transcript from the upstream T7promoter. The DNA was subsequently purified in two phenol:chloroform:IAAextractions, followed by an EtOH precipitation. The linearized DNApellet was dried and resuspended in nuclease-free water for use in an invitro transcription reaction. The in vitro transcription reaction wasperformed using the Megascript T7 Kit (Ambion). A total of 1 ug oflinearized DNA was aliquoted into a solution containing a finalconcentration of 1× Reaction Buffer, 1× Enzyme Mix and 7.5 mM of ATP,UTP, CTP and GTP. The reaction was incubated at 37° C. for 4 hours in anair incubator. Following the incubation, 1 U/1□g DNA of RQ1 DNase enzyme(Promega) was added to the reaction and incubated at 37° C. for 2 hours.The newly synthesized RNA was purified using the RNeasy Kit (Qiagen).Following the manufacturer's protocol, the RNA was bound to the RNeasycolumn and an additional DNase digest was performed using 1 U ofRNase-free DNase (Qiagen) for 1 hour at 25° C. The RNA was eluted innuclease free water and stored at −80° C.

Example 6 Electroporation of RNA into Huh-7 Cells

Five □g of replicon RNA was electroporated into 5×10⁶ cells of thehepatoma cell line, Huh-7. Briefly, Huh-7 cells were passed the daybefore the electroporation and grown to 50% confluency. Huh-7 cells werepelleted, washed, counted and resuspended to a final concentration of1×10⁷ cells/ml in Opti-MEM media (Invitrogen). A total of 5 □g of RNAwas aliquoted into a pre-chilled cuvette on ice. A 0.2 ml aliquot of thecell suspension was then added to the cuvette containing the RNA. TheRNA was immediately electroporated into the Huh-7 cells using the GenePulser (Bio-Rad), adjusted to deliver one pulse of 0.2 kV, 100 ohms and960 □FD. The cuvettes were chilled on ice for 10 minutes to allow thecells to recover. The cells were plated on a 100 mm tissue culture platein complete media. Selection media containing either 0.5 to 1.0 mg/ml ofG418 (Invitrogen) was added to the cells 24-48 hourspost-electroporation.

Example 7 Analysis of Replicons by Western Blot Analysis

Total cell lysates were harvested from replicon cells in 1.1× LDS Buffer(Invitrogen). The lysates were heated for 10 minutes in the presence ofa reducing agent. The lysates were run on a 10% Bis-Tris NuPagepolyachrylamide gel (Invitrogen) in 1× MOPS buffer as recommended by themanufacturer. Protein transfer to PVDF (Invitrogen) membrane wasperformed using the Semi-Dry Trans Blot System (Bio-Rad). Followingtransfer, the blot was rinsed once with PBS containing 0.5% Tween-20(PBS-Tween). The blot was blocked in PBS-Tween containing 5% non-fatmilk for 1 hour at room temperature with gently agitation. The blot wasrinsed quickly with two washes of PBS-Tween, followed by two ten minutePBS-Tween washes with gentle agitation. The primary antibody incubationto detect HCV NS5a protein utilized an □-NS5a rabbit polyclonal antibodydilued 1:2500 in PBS-Tween. The incubation was conducted for 1 hour atroom temperature with gentle agitation. The □-NS5a antibody was removedand the blot was rinsed quickly with two washes of PBS-Tween, followedby two 10 minute PBS-Tween washes with gentle agitation. A secondaryantibody incubation was performed using a HRP conjugated □-rabbit IgGantibody (Amersham) diluted in 1:5000 in PBS-Tween. Again, theincubation was done at room temperature for 1 hour with gentleagitation. Following the secondary antibody incubation, the blot wasrinsed quickly with two washes of PBS-Tween, followed by two ten minutePBS-Tween washes with gentle agitation. The blot was incubated in SuperSignal Chemiluminescent Reagent (Pierce) following the manufacturer'sprotocol and exposed to film (Amersham).

Example 8 Isolation of Genomic DNA

Genomic DNA was isolated using DNeasy Tissue Kit (Qiagen) according tothe manufacturer's protocol. The experiments to determine possiblegenomic incorporation of the neomycin resistance gene was performedusing PCR. Primers Ralf Neo 5′TCA AGA CCG ACC TGT CCG GTG CCC [SEQ IDNO:24] and Ralf Neo 3′CTT GAG CCT GGC GAA CAG TTC GGC [SEQ ID NO:25] toamplify a 380 bp product form 100 ng of genomic DNA. All PCR reactionsutilized 2.5 U of PFU Turbo polymerase (Stratagene) per 100 ul reaction.The PCR reactions contained a final primer and dNTP concentration of 250nM and 100 □M, respectively. In addition, the final bufferconcentrations comprised 20 mM Tris-HCl (pH 8.8), 2 mM MgSO₄, 10 mM KCl,10 mM (NH4)₂SO₄, 0.1% Triton X-100, and 0.1 mg/ml nuclease free BSA.Control primers GAPDH for ACC ACA GTC CAT GCC ATC AC [SEQ ID NO:26] andGAPDH rev TCC ACC ACC CTG TTG CTG TA [SEQ ID NO:27] were used todemonstrate the presence of intact genomic DNA in each PCR reaction.

Example 9 Analysis of Replicon Copy Number by TaqMan

Cells were trypinized and counted to determine cell number. The totalcellular RNA was isolated using RNeasy Mini Kit (Qiagen) following themanufacturer's protocol. The RNA was stored at −80° C. or assayed byTaqMan quantitative RT-PCR. For analysis by TaqMan PCR, a master mix wasprepared using TaqMan EZ RT-PCR Kit (Applied Biosystems #403028), TaqManPDAR Control Reagent Human Cyclophilin (Applied Biosystems #4310883E),custom primer Neo^(R) fwd CCG GCT ACC TGC CCA TTC [SEQ ID NO:28](Invitrogen), custom primer Neo^(R) rev CCA GAT CAT CCG ATC GAC AAG [SEQID NO:29] (Invitrogen), and custom probe Neo^(R) probe 5′FAM-ACA TCG CATCGA GCG AGC ACG TAC-TAMRA 3′ [SEQ ID NO:30] (Biosource International).Master mix concentrations were as follows: 1× TaqMan EZ Buffer, 3 mMMn(Oac)₂, 0.3 mM dATP, 0.3 mM dCTP, 0.3 mM dGTP, 0.6 mM dUTP, 0.2 mMNeo^(R) fwd, 0.2 mM Neo^(R) Rev, 0.1 mM Neo^(R) probe, 1× CyclophilinMix, 0.1 Unit/□l rTth DNA Polymerase, 0.01 Unit/□l AmpErase UNG, and H₂Oto 40 □l. A total of 40 □l of master mix was added to wells of a 96-tubeoptical plate (Applied Biosystems #N801-0560), followed by 10 □l of RNAsample at a concentration of 5 ng/□l. The plate was covered with anoptical adhesive cover (Applied Biosystems #4311971) and mixed byrepeated inversion several times, followed by a brief centrifuge spin.The plate was placed in an AB17700 (Applied Biosystems) and the entireplate was set to FAM dye layer for unknown, and to the VIC dye layer forcontrol. The cycling parameters were set to 50° C, 2 min.; 60° C., 30min.; 95° C., 5 min.; (94° C., 20 sec.; 55° C., 1 min.) 40 cycles, withan exposure time of 10 milliseconds and spectral compensation. Data wasanalyzed by leaving the baseline to default level on both layers, andset a threshold to an equal value for both dye layers. The data wasexported to Microsoft Excel for further analysis. To determine repliconcopy number per cell, a linear regression curve for the known copynumber Neo^(R) standards was established by plotting the Cycle Thresholdvalues (Ct) versus the log of copy number for each Neo^(R) standard. Thecopy number for each replicon sample was calculated by taking thesample's Ct value, minus the line intercept, divided by the slope of theline. TABLE 3 Polynucleotide Sequences (A) Sequences from HCV H77Replicons BB7-F1 [SEQ ID NO: 2]GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCGTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATGTCACGTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCAGTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTAcACCAATGTGGACCAAGACCTTGTGGGCTGGCCCGCTCCTCAAGGTTCCCGCTCATTGACACCCTGTACCTGCGGCTCCTCGGACCTTTACCTGGTCACGAGGCACGCCGATGTCATTCCCGTGCGCCGGCGAGGTGATAGCAGGGGTAGCCTGCTTTCGCCCCGGCCCATTTCCTACTTGAAAGGCTCCTCGGGGGGTCCGCTGTTGTGCCCCGCGGGACACGCCGTGGGCCTATTCAGGGCCGCGGTGTGCACCCGTGGAGTGGCTAAAGCGGTGGACTTTATCCCTGTGGAGAACCTAGGGACAACCATGAGATCCCCGGTGTTCACGGACAACTCCTCTCCACCAGCAGTGCCCCAGAGCTTCCAGGTGGCCCACCTGCATGCTCCCACCGGCAGCGGTAAGAGCACCAAGGTCCCGGCTGCGTACGCAGCCCAGGGCTACAAGGTGTTGGTGCTCAACCCCTCTGTTGCTGCAACGCTGGGCTTTGGTGCTTACATGTCCAAGGCCCATGGGGTTGATCCTAATATCAGGACCGGGGTGAGAACAATTACCACTGGCAGCCCCATCACGTACTCCACCTACGGCAAGTTCCTTGCCGACGGCGGGTGCTCAGGAGGTGCTTATGACATAATAATTTGTGACGAGTGCCACTCCACGGATGCCACATCCATCTTGGGCATCGGCACTGTCCTTGACCAAGCAGAGACTGCGGGGGCGAGACTGGTTGTGCTCGCCACTGCTACCCCTCCGGGCTCCGTCAGTGTGTCCCATCCTAACATCGAGGAGGTTGCTCTGTCCACCACCGGAGAGATCCCCTTTTACGGCAAGGCTATCCCCCTCGAGGTGATCAAGGGGGGAAGACATCTCATCTTCTGCCACTCAAAGAAGAAGTGCGACGAGCTCGCCGCGAAGCTGGTCGCATTGGGCATCAATGCCGTGGCCTACTACCGCGGTCTTGACGTGTGTGTCATCCCGACCAGCGGCGATGTTGTCGTCGTGTCGACCGATGCTCTCATGACTGGCTTACCGGCGACTTCGACTCTGTGATAGACTGCAACACGTGTGTCACTCAGACAGTCGATTTCAGCCTTGACCCTACCTTTACCATTGAGACAACCACGCTCCCCCAGGATGCTGTCTCCAGGACTCAACGCCGGGGCAGGACTGGCAGGGGGAAGCCAGGCATCTATAGATTTGTGGCACCGGGGGAGCGCCCCTCCGGCATGTTCGACTCGTCCGTCCTCTGTGAGTGCTATGACGCGGGCTGTGCTTGGTATGAGCTCACGCCCGCCGAGACTACAGTTAGGCTACGAGCGTACATGAACACCCCGGGGCTTCCCGTGTGCCAGGACCATCTTGAATTTTGGGAGGGCGTCTTTACGGGCCTCACTCATATAGATGCCCACTTTTTATCCCAGACAAAGCAGAGTGGGGAGAACTTTCCTTACCTGGTAGCGTACCAAGCCACCGTGTGCGCTAGGGCTCAAGCCCCTCCCCCATCGTGGGACCAGATGTGGAAGTGTTTGATCCGCCTTAAACCCACCCTCCATGGGCCAACACCCCTGCTATACAGACTGGGCGCTGTTCAGAATGAAGTCACCCTGACGCACCCAATCACCAAATACATCATGACATGCATGTCGGCCGACCTGGAGGTCGTCACGAGCACCTGGGTGCTCGTTGGCGGCGTCCTGGCTGCTCTGGCCGCGTATTGCCTGTCAACAGGCTGCGTGGTCATAGTGGGCAGGATCGTCTTGTCCGGGAAGCCGGCAATTATACCTGACAGGGAGGTTCTCTACCAGGAGTTCGATGAGATGGAAGAGTGCTCTCAGCACTTACCGTACATCGAGCAAGGGATGATGCTCGCTGAGCAGTTCAAGCAGAAGGCCCTCGGCCTCGTGCAGACCGCGTCCCGCCATGCAGAGGTTATCACCCCTGCTGTCCAGACCAACTGGCAGAAACTCGAGGTCTTTTGGGCGAAGCACATGTGGAATTTCATCAGTGGGATACAATACTTGGCGGGCCTGTCAACGCTGCCTGGTAACCCCGCCATTGCTTCATTGATGGCTTTTACAGCTGCCGTCACCAGCCCACTAACCACTGGCCAAACCCTCCTCTTCAACATATTGGGGGGGTGGGTGGCTGCCCAGCTCGCCGCCCCCGGTGCCGCTACTGCCTTTGTGGGTGCTGGCCTAGCTGGCGCCGCCATCGGCAGCGTTGGACTGGGGAAGGTCCTCGTGGACATTCTTGCAGGGTATGGCGCGGGCGTGGCGGGAGCTCTTGTAGCATTCAAGATCATGAGCGGTGAGGTCCCCTCCACGGAGGACCTGGTCAATCTGCTGCCCGCCATCCTCTCGCCTGGAGCCCTTGTAGTCGGTGTGGTCTGCGCAGCAATACTGCGCCGGCACGTTGGCCCGGGCGAGGGGGCAGTGCAATGGATGAACCGGCTAATAGCCTTCGCCTCCCGGGGGAACCATGTTTCCCCCACGCACTACGTGCCGGAGAGCGATGCAGCCGCCCGCGTCACTGCCATACTCAGCAGCCTCACTGTAACCCAGCTCCTGAGGCGACTGCATCAGTGGATAAGCTCGGAGTGTACCACTCCATGCTCCGGTTCCTGGCTAAGGGACATCTGGGACTGGATATGCGAGGTGCTGAGCGACTTTAAGACCTGGGTGAAAGCCAAGCTCATGCCACAACTGCCTGGGATTCCCTTTGTGTCCTGCCAGCGCGGGTATAGGGGGGTCTGGCGAGGAGACGGCATTATGCACACTCGCTGCCACTGTGGAGCTGAGATCACTGGACATGTCAAAAACGGGACGATGAGGATCGTCGGTCCTAGGACCTGCAGGAACATGTGGAGTGGGACGTTCCCCATTAACGCCTACACCACGGGCCCTGTACTCCCCTTCCTGCGCCGAACTATAAGTTCGCGCTGTGGAGGGTGTCTGCAGAGGAATACGTGGAGATAAGGCGGGTGGGGGACTTCCACTACGTATCGGGTATGACTACTGACAATCTTAAATGCCCGTGCCAGATCCCATCGCCCGAATTCTTCACAGAAGTGGATGGGGTGCGGTTGCACAGGTACGCTCCAGCGTGCAAACCCCTCCTACGGGAGGAGGTCACATTCCTGGTCGGGCTCAATCAATACCTGGTTGGGTCACAGCTCCCATGCGAGCCCGAACCGGACGTAGCAGTGCTCACTTCCATGCTCACCGACCCCTCCCACATTACGGCGGAGACGGCTAAGCGTAGGCTGGCCAGGGGATCTCCCCCCTCCTTGGCCAGCTCATCAGCTATCCAGCTGTCTGCGCCTTCCTTGAAGGCAACATGCACTACCCGTCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCCTGTGGCGGCAGGAGATGGGCGGGAACATCACCCGCGTGGAGTCAGAAAATAAGGTAGTAATTTTGGACTCTTTCGAGCCGCTCCAAGCGGAGGAGGATGAGAGGGAAGTATCCGTTCCGGCGGAGATCCTGCGGAGGTCCAGGAAATTCCCTCGAGCGATGCCCATATGGGCACGCCCGGATTACAACCCTCCACTGTTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCAGTGGTACACGGGTGTCCATTGCCGCCTGCCAAGGCCCCTCCGATACCACCTCCACGGAGGAAGAGGACGGTTGTCCTGTCAGAATCTACCGTGTCTTCTGCCTTGGCGGAGCTCGCCACAAAGACCTTCGGCAGGTCCGAATCGTCGGCCGTCGACAGCGGCACGGCAACGGCCTCTCCTGACCAGCCCTCCGACGACGGCGACGCGGGATCCGACGTTGAGTCGTACTCCTCCATGCCCCCCCTTGAGGGGGAGCCGGGGGATCCCGATCTCAGCGACGGGTCTTGGTCTACCGTAAGCGAGGAGGCTAGTGAGGACGTCGTCTGCTGCTCGATGTCCTACACATGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAACCAAGCTGCCCATCAATGCACTGAGCAACTCTTTGCTCCGTCACCACAACTTGGTCTATGCTACAACATCTCGCAGCGCAAGCCTGCGGCAGAAGAAGGTCACCTTTGACAGACTGCAGGTCCTGGACGACCACTACCGGGACGTGCTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAACTTCTATCCGTGGAGGAAGCCTGTAAGCTGACGCCCCCACATTCGGCCAGATCTAAATTTGGCTATGGGGCAAAGGACGTCCGGAACCTATCCAGCAAGGCCGTTAACCACATCCGCTCCGTGTGGAAGGACTTGCTGGAAGACACTGAGACACCAATTGACACCACCATCATGGCAAAAAATGAGGTTTTCTGCGTCCAACCAGAGAAGGGGGGCCGCAAGCCAGCTCGCCTTATCGTATTCCCAGATTTGGGGGTTCGTGTGTGCGAGAAAATGGCCCTTTACGATGTGGTCTCCACCCTCCCTCAGGCCGTGATGGGCTCTTCATACGGATTCCAATACTCTCCTGGACAGCGGGTCGAGTTCCTGGTGAATGCCTGGAAAGCGAAGAAATGCCCTATGGGCTTCGCATATGACACCCGCTGTTTTGACTCAACGGTCACTGAGAATGACATCCGTGTTGAGGAGTCAATCTACCAATGTTGTGACTTGGCCCCCGAAGCCAGACAGGCCATAAGGTCGCTCACAGAGCGGCTTTACATCGGGGGCCCCCTGACTAATTCTAAAGGGCAGAACTGCGGCTATCGCCGGTGCCGCGCGAGCGGTGTACTGACGACCAGCTGCGGTAATACCCTCACATGTTACTTGAAGGCCGCTGCGGCCTGTCGAGCTGCGAAGCTCCAGGACTGCACGATGCTCGTATGCGGAGACGACCTTGTCGTTATGTGTGAAAGCGCGGGGACCCAAGAGGACGAGGCGAGCCTACGGGCCTTCACGGAGGCTATGACTAGATAGTCTGCCCCCCCTGGGGACCCGCCAAACCAGAATACGACTTGGAGTTGATAACATCATGCTCCTCCAATGTGTCAGTCGCGCACGATGCATCTGGCAAAAGGGTGTACTATCTCACCCGTGACCCCACCACCCCCCTTGCGCGGGCTGCGTGGGAGACAGCTAGACACACTCCAGTCAATTCCTGGCTAGGCAACATCATCATGTATGCGCCCACCTTGTGGGCAAGGATGATCCTGATGACTCATTTCTTCTCCATCCTTCTAGCTCAGGAACAACTTGAAAAAGCCCTAGATTGTCAGATCTACGGGGCCTGTTACTCCATTGAGCCACTTGACCTACCTCAGATCATTCAACGACTCCATGGCCTTAGCGCATTTTCACTCCATAGTTACTCTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCGCCCTTGCGAGTCTGGAGACATCGGGCCAGAAGTGTCCGCGCTAGGCTACTGTCCCAGGGGGGGAGGGCTGCCACTTGTGGCAAGTACCTCTTCAACTGGGCAGTAAGGACCAAGCTCAAACTCACTCCAATCCCGGCTGCGTCCCAGTTGGATTATCCAGCTGGTTCGTTGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCTGGTTCATGTGGTGCCTACTCCTACTTTCTGTAGGGGTAGGCATCTATCTACTCCCCAACCGATGAACGGGGACCTAAACACTCCAGGCCAATAGGCCATCCTGTTTTTTTCCCTTTTTTTTTTTCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTCCTTTTTTTTTCCTCTTTTTTTCCTTTTCTTTCCTTTGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCTTGACTGCAGAGAGTGCTGATACTGGCCT CTCTGCAGATCAAGTBB7-F1/F2: [SEQ ID NO: 3]GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTGTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATGTCCTGTCATCTCACGTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTGTGGAAAGAGTCAAATGGCTGTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTAcACCAATGTGGACCAAGACCTTGTGGGCTGGCCCGCTCCTCAAGGTTCCCGCTCATTGACACCCTGTACCTGCGGCTCCTCGGACCTTTACCTGGTCACGAGGCACGCCGATGTCATTCCCGTGCGCCGGCGAGGTGATAGCAGGGGTAGCCTGCTTTCGCCCCGGCCCATTTCCTACTTGAAAGGCTCGTCGGGGGGTCCGCTGTTGTGCCCCGCGGGACACGCCGTGGGCCTATTCAGGGCCGCGGTGTGCACCCGTGGAGTGGCTAAAGCGGTGGACTTTATCCCTGTGGAGAACCTAGGGACAACCATGAGATCCCCGGTGTCACGGACAACTCCTCTCCACCAGCAGTGCCCCAGAGCTTCCAGGTGGCCCACCTGCATGCTCCCACCGGCAGCGGTAAGAGCACCAAGGTCCCGGCTGCGTACGCAGCCCAGGGCTACAAGGTGTTGGTGCTCAACCCCTCTGTTGCTGCAACGCTGGGCTTTGGTGCTTACATGTCCAAGGCCCATGGGGTTGATCCTAATATCAGGACCGGGGTGAGAACAATTACCACTGGCAGCCCCATCACGTACTCCACCTACGGCAAGTTCCTTGCCGACGGCGGGTGCTCAGGAGGTGCTTATGACATAATAATTTGTGACGAGTGCCACTCCACGGATGCCACATCCATCTTGGGCATCGGCACTGTCCTTGACCAAGCAGAGACTGCGGGGGCGAGACTGGTTGTGCTCGCCACTGCTACCCCTCCGGGCTCCGTCACTGTGTCCCATCCTAACATCGAGGAGGTTGCTCTGTCCACCACCGGAGAGATCCCCTTTTACGGCAAGGCTATCCCCCTCGAGGTGATCAAGGGGGGAAGACATCTCATCTTCTGCCACTCAAAGAAGAAGTGCGACGAGCTCGCCGCGAAGCTGGTCGCATTGGGCATCAATGCCGTGGCCTACTACCGCGGTCTTGACGTGTCTGTCATCCCGACCAGCGGCGATGTTGTCGTCGTGTCGACCGATGCTCTCATGACTGGCTTTACCGGCGACTTCGACTCTGTGATAGACTGCAACACGTGTGTCACTCAGACAGTCGATTTCAGCCTTGACCCTACCTTTACCATTGAGACAACCACGCTCCCCCAGGATGCTGTCTCCAGGACTCAACGCCGGGGCAGGACTGGCAGGGGGAAGCCAGGCATCTATAGATTTGTGGCACCGGGGGAGCGCCCCTCCGGCATGTTCGACTCGTCCGTCCTCTGTGAGTGCTATGACGCGGGCTGTGCTTGGTATGAGCTCACGCCCGCCGAGACTACAGTTAGGCTACGAGCGTACATGAACACCCCGGGGCTTCCCGTGTGCCAGGACCATCTTGAATTTTGGGAGGGCGTCTTTACGGGCCTCACTCATATAGATGCCCACTTTTTATCCCAGACAAAGCAGAGTGGGGAGAACTTTCCTTACCTGGTAGCGTACCAAGCCACCGTGTGCGCTAGGGCTCAAGCCCGTCCCCCATCGTGGGACCAGATGTGGAAGTGTTTGATCCGCCTTAAACCCACCCTCCATGGGCCAACACCCCTGCTATACAGACTGGGCGCTGTTCAGAATGAAGTCACCCTGACGCACCCAATCACCAAATACATCATGACATGCATGTCGGCCGACCTGGAGGTCGTCACGAGCACCTGGGTGCTCGTTGGCGGCGTCCTGGCTGCTCTGGCCGCGTATTGCCTGTCAACAGGCTGCGTGGTCATAGTGGGCAGGATCGTCTTGTCCGGGAAGCCGGCAATTATACCTGACAGGGAGGTTCTCTACCAGGAGTTCGATGAGATGGAAGAGTGCTCTCAGCACTTACCGTACATCGAGCAAGGGATGATGCTCGCTGAGCAGTTCAAGCAGAAGGCCCTCGGCCTCCTGCAGACCGCGTCCCGCCATGCAGAGGTTATCACCCCTGCTGTCCAGACCAACTGGCAGAAACTCGAGGTCTTTTGGGCGAAGCACATGTGGAATTTCATCAGTGGGATACAATACTTGGCGGGCCTGTCAACGCTGCCTGGTAACCCCGCCATTGCTTCATTGATGGCTTTTACAGCTGCCGTCACCAGCCCACTAACCACTGGCCAAACCCTCCTCTTCAACATATTGGGGGGGTGGGTGGCTGCCCAGGTCGCCGCCCCCGGTGCCGCTACTGCCTTTGTGGGTGCTGGCCTAGCTGGCGCCGCCATCGGCAGCGTTGGACTGGGGAAGGTCCTCGTGGACATTCTTGCAGGGTATGGCGCGGGCGTGGCGGGAGCTCTTGTAGCATTCAAGATCATGAGCGGTGAGGTCCCCTCCACGGAGGACCTGGTCAATCTGCTGCCCGCCATCCTCTCGCCTGGAGCCCTTGTAGTCGGTGTGGTCTGCGCAGCAATACTGCGCCGGCACGTTGGCCCGGGCGAGGGGGCAGTGCAATGGATGAACCGGCTAATAGCCTTCGCCTCCCGGGGGAACCATGTTTCCCCCACGCACTACGTGCCGGAGAGCGATGCAGCCGCCCGCGTCACTGCCATACTCAGCAGCCTCACTGTAACCCAGCTCCTGAGGCGACTGCATCAGTGGATAAGCTCGGAGTGTACCACTCCATGCTCCGGTTCCTGGCTAAGGGACATCTGGGACTGGATATGCGAGGTGCTGAGCGACTTTAAGACCTGGCTGAAAGCCAAGCTCATGCCACAACTGCCTGGGATTCCCTTTGTGTCCTGCCAGCGCGGGTATAGGGGGGTCTGGCGAGGAGACGGCATTATGCACACTCGCTGCCACTGTGGAGCTGAGATCACTGGACATGTCAAAAAACGGGACGATGAGGATCGTCGGTCCTAGGACCTGCAGGAACATGTGGAGTGGGACGTTCCCCATTAACGCCTACACCACGGGCCCCTGTACTCCCCTTCCTGCGCCGAACTATAAGTTCGCGCTGTGGAGGGTGTCTGCAGAGGAATACGTGGAGATAAGGCGGGTGGGGGACTTCCACTACGTATCGGGTATGACTACTGACAATCTTAAATGCCCGTGCCAGATCCCATCGCCCGAATTcTTCACAGAATTGGACGGGGTGCGCCTACACAGGTTTGCGCCCCCTTGCAAGCCCTTGCTGCGGGAGGAGGTATCATTCAGAGTAGGACTCCACGAGTACCCGGTGGGGTCGCAATTACCTTGCGAGCCCGAACCGGACGTAGCCGTGTTGACGTCCATGCTCACTGATCCCTCCCATATAACAGCAGAGGCGGCCGGGAGAAGGTTGGCGAGAGGGTCACCCCCTTCTATGGCCAGCTCCTCGGCTAtCCAGCTGTCCGCTCCATCTCTCAAGGCAACTTGCACCGCCAACCATGACTCCCCTGACGCCGAGCTCATAGAGGCTAACCTCCTGTGGAGGCAGGAGATGGGCGGCAACATCACCAGGGTTGAGTCAGAGAACAAAGTGGTGATTCTGGACTCCTTCGATCCGCTTGTGGCAGAGGAGGATGAGCGGGAGGTCTCCGTACCTGCAGAAATTCTGCGGAAGTCTCGGAGATTCGCCCGGGCCCTGCCCGTCTGGGCGCGGCCGGACTACAACCCCCCGCTAGTAGAGACGTGGAAAAAGCCTGACTACGAACCACCTGTGGTCCATGGCTGCCCGCTACCACCTCCACGGTCCCCTCCTGTGCCTCCGCCTCGGAAAAAGCGTACGGTGGTCCTCACCGAATCAACCCTATCTACTGCCTTGGCCGAGCTTGCCACCAAAAGTTTTGGCAGCTCCTCAACTTCCGGCATTACGGGCGACAATACGACAACATCCTCTGAGCCCGCCCCTTCTGGCTGCCCCCCCGACTCCGACGTTGAGTCCTATTCTTCCATGCCCCCCCTGGAGGGGGAGCCTGGGGATCCGGATCTCAGCGACGGGTCATGGTCGACGGTCAGTAGTGGGGCCGACACGGAAGATGTCGTGTGCTGCTCAATGTCTTATTCCTGGACAGGCGCACTCGTCACCCCGTGCGCTGCGGAAGAACAAAAACTGCCCATCAACGCACTGAGCAACTCGTTGCTACGCCATCACAATCTGGTGTATTCCACCACTTCACGCAGTGCTTGCCAAAGGCAGAAGAAAGTCACATTTGACAGACTGCAAGTTCTGGACAGCCATTACCAGGACGTGCTCAAGGAGGTCAAAGCAGCGGCGTCAAAAGTGAAGGCTAACTTGCTATCCGTAGAGGAAGCTTGCAGCCTGACGCCCCCACATTCAGCCAAATCCAAGTTTGGCTATGGGGCAAAAGACGTCCGTTGCCATGCCAGAAAGGCCGTAGCCCACATCAACTCCGTGTGGAAAGACCTTCTGGAAGACAGTGTAACACCAATTGACACCACCATCATGGCAAAAAATGAGGTTTTCTGCGTCCAACCAGAGAAGGGGGGCCGCAAGCCAGCTCGCCTTATCGTATTCCCAGATTTGGGGGTTCGTGTGTGCGAGAAAATGGCCCTTTACGATGTGGTCTCCACCCTCCCTCAGGCCGTGATGGGCTCTTCATACGGATTCCAATACTCTCCTGGACAGCGGGTCGAGTTCCTGGTGAATGCCTGGAAAGCGAAGAAATGCCCTATGGGCTTCGCATATGACACCCGCTGTTTTGACTCAACGGTCACTGAGAATGACATCCGTGTTGAGGAGTCAATCTACCAATGTTGTGACTTGGCCCCCGAAGCCAGACAGGCCATAAGGTCGCTCACAGAGCGGCTTTACATCGGGGGCCCCCTGACTAATTCTAAAGGGCAGAACTGCGGCTATCGCCGGTGCCGCGCGAGCGGTGTACTGACGACCAGCTGCGGTAATACCCTCACATGTTACTTGAAGGCCGCTGCGGCGTGTCGAGCTGCGAAGCTCCAGGAGTGCACGATGCTCGTATGCGGAGACGACCTTGTCGTTATCTGTGAAAGCGCGGGGACCCAAGAGGACGAGGCGAGCCTACGGGCCTTCACGGAGGCTATGAGTAGATACTCTGCCCCCCCTGGGGACCCGCCCAAACCAGAATACGACTTGGAGTTGATAACATCATGCTCCTCCAATGTGTCAGTCGCGCACGATGCATCTGGCAAAAGGGTGTACTATCTCACCCGTGACCCCACCACCCCCCTTGCGCGGGCTGCGTGGGAGACAGCTAGACACACTCCAGTCAATTCCTGGCTAGGCAACATCATCATGTATGCGCCCACCTTGTGGGCAAGGATGATCCTGATGACTCATTTCTTCTCCATCCTTCTAGCTCAGGAACAACTTGAAAAAGCCCTAGATTGTCAGATCTACGGGGCCTGTTACTCCATTGAGCCACTTGACCTACCTCAGATCATTCAACGACTCCATGGCCTTAGCGCATTTTCACTCCATAGTTACTCTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCGCCCTTGCGAGTCTGGAGACATCGGGCCAGAAGTGTCCGCGCTAGGCTACTGTCCCAGGGGGGGAGGGCTGCCACTTGTGGCAAGTACCTCTTCAACTGGGCAGTAAGGACCAAGCTCAAACTCACTCCAATCCCGGCTGCGTCCCAGTTGGATTTATCCAGCTGGTTCGTTGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCTGGTTCATGTGGTGCCTACTCCTACTTTCTGTAGGGGTAGGCATCTATCTACTCCCCAACCGATGAACGGGGACCTAAACACTCCAGGCCAATAGGCCATCCTGTTTTTTTCCCTTTTTTTTTTTCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTCCTTTTTTTTTCCTCTTTTTTTCCTTTTCTTTCCTTTGGTGGCTCCATCTTAGCCCTAGTCACGGGTAGCTGTGAAAGGTCCGTGAGCCGCTTGACTGCAGAGAGTGCTGATACTGGCCTCTCTGCAGATCAAGT BB7-F3: [SEQ ID NO: 4]GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCGTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATGTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGGTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTGGACCAGGACCTCGTCGGCTGGCAAGCGCCCCCCGGGGCGCGTTCCTTGACACCATGCACCTGCGGCAGCTCGGACCTTTACTTGGTCACGAGGCATGCCGATGTCATTCCGGTGCGCCGGCGGGGCGACAGCAGGGGGAGCGTAGTGTCCCCCAGGCCCGTCTCCTACTTGAAGGGCTCTTCGGGCGGTCCACTGCTCTGCCCCTCGGGGCACGCTGTGGGCATCTTTCGGGCTGCCGTGTGCACCCGAGGGGTTGCGAAGGCGGTGGACTTTGTACCCGTCGAGTCTATGGAAACCACTATGCGGTCCCCGGTCTTCACGGACAACTCGTCCCCTCCGGCCGTACCGCAGACATTCCAGGTGGCCCATCTACACGCCCCTACTGGTAGCGGCAAGAGCACTAAGGTGCCGGCTGCGTATGCAGCCCAAGGGTATAAGGTGCTTGTCCTGAACCCGTCCGTCGCCGCCACCCTAGGTTTCGGGGCGTATATGTCTAAGGCACATGGTATCGACCCTAACATCAGAACCGGGGTAAGGACCATCACCACGGGTGCCCCCATCACGTACTCCACCTATGGCAAGTTTCTTGCCGACGGTGGTTGCTCTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAACTGACTCGACCACTATCCTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGACTCGTCGTGCTCGCCACCGCTACGCCTCCGGGATCGGTCACCGTGCCACATCCAAACATCGAGGAGGTGGCTCTGTCCAGCACTGGAGAAATCCCCTTTTATGGCAAAGCCATCCCCATCGAGACCATCAAGGGGGGGAGGCACCTCATTTTCTGCCATTCCAAGAAGAAATGTGATGAGCTCGCCGCGAAGCTGTCCGGCCTCGGACTCAATGCTGTAGCATATTACCGGGGCCTTGATGTATCCGTCATACCAACTAGCGGAGACGTCATTGTCGTAGCAACGGACGCTCTAATGACGGGCTTTACCGGCGATTTCGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCCTGGACCCGACCTTCACCATTGAGACGACGACCGTGCCACAAGACGCGGTGTCACGCTCGCAGCGGCGAGGCAGGACTGGTAGGGGCAGGATGGGCATTTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCCTCGGTTCTGTGCGAGTGCTATGACGCGGGCTGTGCTTGGTACGAGCTCACGCCCGCCGAGACCTCAGTTAGGTTGCGGGCTTACCTAAACACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGAGCGTCTTTACAGGCCTCACCCACATAGACGCCCATTTCTTGTCCCAGACTAAGCAGGCAGGAGACAACTTCCCCTACCTGGTAGCATACCAGGCTACGGTGTGCGCCAGGGCTCAGGCTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTAAAGCCTACGCTGCACGGGCCAACGCCCCTGCTGTATAGGCTGGGAGCCGTTCAAAACGAGGTTACTACCACACACCCCATAACCAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACGAGCACCTGGGTGCTGGTAGGCGGAGTCCTAGCAGCTCTGGCCGCGTATTGCCTGACAACAGGCAGCGTGGTCATTGTGGGCAGGATCATCTTGTCCGGAAAGCCGGCCATCATTCCCGACAGGGAAGTCCTTTACCGGGAGTTCGATGAGATGGAAGAGTGCGCCTCACACCTCCCTTACATCGAACAGGGAATGCAGCTCGCCGAACAATTCAAACAGAAGGCAATCGGGTTGCTGCAAACAGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAATCCAAGTGGCGGACCCTCGAAGCCTTCTGGGCGAAGCATATGTGGAATTTCATCAGCGGGATACAATATTTAGCAGGCTTGTCCACTCTGCCTGGCAACCCCGCGATAGCATCACTGATGGCATTCACAGCCTCTATCACCAGCCCGCTCACCACCCAACATACCCTCCTGTTTAACATCCTGGGGGGATGGGTGGCCGCCCAACTrGCTCCTCCCAGCGCTGCTTCTGCTTTCGTAGGCGCCGGCATCGCTGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTTGTGGATATTTTGGCAGGTTATGGAGCAGGGGTGGCAGGCGCGCTCGTGGCCTTTAAGGTCATGAGCGGCGAGATGCCCTCCACCGAGGACCTGGTTAACCTACTCCCTGCTATCCTCTCCCCTGGCGCCCTAGTCGTCGGGGTCGTGTGCGCAGCGATACTGCGTCGGCACGTGGGCCCAGGGGAGGGGGCTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCCCACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCCTCTCTAGTCTTACCATCACTCAGCTGCTGAAGAGGCTTCACCAGTGGATCAACGAGGACTGCTCCACGCCATGCTCCGGCTCGTGGCTAAGAGATGTTTGGGATTGGATATGCACGGTGTTGACTGATTTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCGATTGCCGGGAGTCCCCTTCTTCTCATGTCAACGTGGGTACAAGGGAGTCTGGCGGGGCGACGGCATCATGCAAACCACCTGCCCATGTGGAGCACAGATCACCGGACATGTGAAAAACGGTTCCATGAGGATCGTGGGGCCTAGGACCTGTAGTAACACGTGGCATGGAACATTCCCCATTAACGCGTACACCACGGGCCCCTGCACGCCCTCCCCGGCGCCAAATTATTCTAGGGCGCTGTGGCGGGTGGCTGCTGAGGAGTACGTGGAGGTTACGCGGGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCGTGTCAGGTTCCGGCCCCCGAATTCTTCACAGAAGTGGATGGGGTGCGGTTGCACAGGTACGCTCCAGCGTGCAAACCCCTCCTACGGGAGGAGGTCACATTCCTGGTCGGGCTCAATCAATACCTGGTTGGGTCACAGCTCCCATGCGAGCCCGAACCGGACGTAGCAGTGCTCACTTCCATGCTCACCGACCCCTCCCACATTACGGCGGAGACGGCTAAGCGTAGGCTGGCCAGGGGATCTCCCCCCTCCTTGGCCAGCTCATCAGCTATCCAGCTGTCTGCGCCTTCCTTGAAGGCAACATGCACTACCCGTCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCCTGTGGCGGCAGGAGATGGGCGGGAACATCACCCGCGTGGAGTCAGAAAATAAGGTAGTAATTTTGGACTCTTTCGAGCCGCTCCAAGCGGAGGAGGATGAGAGGGAAGTATCCGTTCCGGCGGAGATCCTGCGGAGGTCCAGGAAATTCCCTCGAGCGATGCCCATATGGGCACGCCCGGATTACAACCCTCCACTGTTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCAGTGGTACACGGGTGTCCATTGCCGCCTGCCAAGGCCCCTCCGATACCACCTCCACGGAGGAAGAGGACGGTTGTCCTGTCAGAATCTACCGTGTCTTCTGCCTTGGCGGAGCTCGCCACAAAGACCTTCGGCAGCTCCGAATCGTCGGCCGTCGACAGCGGCACGGCAACGGCCTCTCCTGACCAGCCCTCCGACGACGGCGACGCGGGATCCGACGTTGAGTCGTACTCCTCCATGCCCCCCCTTGAGGGGGAGCCGGGGGATCCCGATCTCAGCGACGGGTCTTGGTGTACCGTAAGCGAGGAGGCTAGTGAGGACGTCGTCTGCTGCTCGATGTCCTACACATGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAACCAAGCTGCCCATCAATGCACTGAGCAACTCTTTGCTCCGTCACCACAACTTGGTCTATGCTACAACATCTCGCAGCGCAAGCCTGCGGCAGAAGAAGGTCACCTTTGACAGACTGCAGGTCCTGGACGACCACTACCGGGACGTGCTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAACTTCTATCCGTGGAGGAAGCCTGTAAGCTGACGCCCCCACATTCGGCCAGATCTAAATTTGGCTATGGGGCAAAGGACGTCCGGAACCTATCCAGCAAGGCCGTTAACCACATCCGCTCCGTGTGGAAGGACTTGCTGGAAGACACTGAGACACCAATtGACACTACCATCATGGCCAAGAACGAGGTTTTCTGCGTTCAGCCTGAGAAGGGGGGTCGTAAGCCAGCTCGTCTCATCGTGTTCCCCGACCTGGGCGTGCGCGTGTGCGAGAAGATGGCCCTGTACGACGTGGTTAGCAAGCTCCCCCTGGCCGTGATGGGAAGCTCCTACGGATTCCAATACTCACCAGGACAGCGGGTTGAATTCCTCGTGCAAGCGTGGAAGTCCAAGAAGACCCCGATGGGGTTCTCGTATGATACCCGCTGTTTTGACTCCACAGTCACTGAGAGCGACATCCGTACGGAGGAGGCAATTTACCAATGTTGTGACCTGGACCCCCAAGCCCGCGTGGCCATCAAGTCCCTCACTGAGAGGCTTTATGTTGGGGGCCCTCTTACCAATTCAAGGGGGGAAAACTGCGGCTACCGCAGGTGCCGCGCGAGCGGCGTACTGACAACTAGCTGTGGTAACACCCTCACTTGCTACATCAAGGCCCGGGCAGCCTGTCGAGCCGCAGGGCTCCAGGACTGCACCATGCTCGTGTGTGGCGACGACTTAGTCGTTATCTGTGAAAGTGCGGGGGTCCAGGAGGACGCGGCGAGCCTGAGAGCCTTCACGGAGGCTATGACCAGGTACTCCGCCCCCCCCGGGGACCCCCCACAACCAGAATACGACTTGGAGCTTATAACATCATGCTCCTCCAACGTGTCAGTCGCCCACGACGGCGCTGGAAAGAGGGTCTACTACCTTACCCGTGACCCTACAACCCCCCTCGCGAGAGCCGCGTGGGAGACAGCAAGACACACTCCAGTCAATTCCTGGCTAGGCAACATAATCATGTTTGCCCCCACACTGTGGGCGAGGATGATACTGATGACCCATTTCTTTAGCGTCCTCATAGCCAGGGATCAGCTTGAACAGGCTCTTAACTGTGAGATCTACGGAGCCTGCTACTCCATAGAACCACTGGATCTACCTCCAATCATTCAAAGACTCCATGGCCTCAGCGCATTTTCACTCCACAGTTACTCTCCAGGTGAAATCAATAGGGTGGCCGCATGCCTCAGAAAACTTGGGGTCCCGCCCTTGCGAGCTTGGAGACACCGGGCCCGGAGCGTCCGCGCTAGGCTTCTGTCCAGAGGAGGCAGGGCTGCCATATGTGGCAAGTACCTCTTCAACTGGGCAGTAAGAACAAAGCTCAAACTCACTCCAATAGCGGCCGCTGGCCGGCTGGACTTGTCCGGTTGGTTCACGGCTGGGTACAGCGGGGGAGACATTTATCACAGCGTGTCTCATGCCCGGCCCCGCTGGTTCTGGTTTTGCCTACTCCTGCTCGCTGCAGGGGTAGGCATCTACCTCCTCCCCAACCGATGAAGGTTGGGGTAAACACTCCGGCCTCTTAAGCCATTTCCTGTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTCTTTCCTTTCCTTCTTTTTTTCCTTTCTTTTTCCCTTCTTTAATGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCATGACTGCAGAGAGTGCTGATACTGGCCTCTGTGCAGA TCAaGT BB7-F3(C):[SEQ ID NO: 5] GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTGTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTGGACCAGGACCTCGTCGGCTGGCAAGCGCCCCCCGGGGCGCGTTCCTTGACACCATGCACCTGCGGCAGCTCGGACCTTTACTTGGTCACGAGGCATGCCGATGTCATTCCGGTGCGCCGGCGGGGCGACAGCAGGGGGAGCCTACTCTCCCCCAGGCCCGTCTCCTACTTGAAGGGCTCTTCGGGCGGTCCACTGCTCTGCCCCTCGGGGCACGCTGTGGGCATCTTTCGGGCTGCCGTGTGCACCCGAGGGGTTGCGAAGGCGGTGGACTTTGTACCCGTCGAGTCTATGGAAACCACTATGCGGTCCCCGGTCTTCACGGACAACTCGTCCCCTCCGGCCGTACCGCAGACATTCCAGGTGGCCCATCTACACGCCCCTACTGGTAGCGGCAAGAGCACTAAGGTGCCGGCTGCGTATGCAGCCCAAGGGTATAAGGTGCTTGTCCTGAACCCGTCCGTCGCCGCCACCCTAGGTTTCGGGGCGTATATGTCTAAGGCACATGGTATCGACCCTAACATCAGAACCGGGGTAAGGACCATCACCACGGGTGCCCCCATCACGTACTCCACCTATGGCAAGTTTCTTGCCGACGGTGGTTGCTCTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAAGTGACTCGACCACTATCCTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGACTCGTCGTGCTCGCCACCGCTACGCCTCCGGGATCGGTCACCGTGCCACATCCAAACATCGAGGAGGTGGCTCTGTCCAGCACTGGAGAAATCCCCTTTTATGGCAAAGCCATCCCCATCGAGACCATCAAGGGGGGGAGGCACCTCATTTTCTGCCATTCCAAGAAGAAATGTGATGAGCTCGCCGCGAAGCTGTCCGGCCTCGGACTCAATGCTGTAGCATATTACCGGGGCCTTGATGTATCCGTCATACCAACTAGCGGAGACGTCATTGTCGTAGCAACGGACGCTCTAATGACGGGCTTTACCGGCGATTTCGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCCTGGACCCGACCTTCACCATTGAGACGACGACCGTGCCACAAGACGCGGTGTCACGCTCGCAGCGGCGAGGCAGGACTGGTAGGGGCAGGATGGGCATTTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCCTCGGTTCTGTGCGAGTGCTATGACGCGGGCTGTGCTTGGTACGAGCTCACGCCCGCCGAGACCTCAGTTAGGTTGCGGGCTTACGTAAACACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGAGCGTCTTTACAGGCCTCACCCACATAGACGCCCATTTCTTGTCCCAGACTAAGCAGGCAGGAGACAACTTCCCCTACCTGGTAGCATACCAGGCTACGGTGTGCGCCAGGGCTCAGGCTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTAAAGCCTACGCTGCACGGGCCAACGCCCCTGCTGTATAGGCTGGGAGCCGTTCAAAACGAGGTTACTACCACACACCCCATAACCAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACGAGCACCTGGGTGCTGGTAGGCGGAGTCCTAGCAGCTCTGGCCGCGTATTGCCTGACAACAGGCAGCGTGGTCATTGTGGGCAGGATCATCTTGTCCGGAAAGCCGGCCATCATTCCCGACAGGGAAGTCCTTTACCGGGAGTTCGATGAGATGGAAGAGTGCGCCTCACACCTCCCTTACATCGAACAGGGAATGCAGCTCGCCGAACAATTCAAACAGAAGGCAATCGGGTTGCTGCAAACAGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAATCCAAGTGGCGGACCCTCGAAGCCTTCTGGGCGAAGCATATGTGGAATTTCATCAGCGGGATACAATATTTAGCAGGCTTGTCCACTCTGCCTGGCAACCCCGCGATAGCATCACTGATGGCATTCACAGCCTCTATCACCAGCCCGCTCACCACCCAACATACCCTCCTGTTTAACATCCTGGGGGGATGGGTGGCCGCCCAACTTGCTCCTCCCAGCGCTGCTTCTGCTTTCGTAGGCGCCGGCATCGCTGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTTGTGGATATTTTGGCAGGTTATGGAGCAGGGGTGGCAGGCGCGCTCGTGGCCTTTAAGGTCATGAGCGGCGAGATGCCCTCCACCGAGGACCTGGTTAACCTACTCCCTGCTATCCTCTCCCCTGGCGCCCTAGTCGTCGGGGTCGTGTGCGCAGCGATACTGCGTCGGCACGTGGGCCCAGGGGAGGGGGCTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCCCACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCCTCTCTAGTCTTACCATCACTCAGCTGCTGAAGAGGCTTCACCAGTGGATCAACGAGGACTGCTCCACGCCATGCTCCGGCTCGTGGCTAAGAGATGTTTGGGATTGGATATGCACGGTGTTGACTGATTTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCGATTGCCGGGAGTCCCCTTCTTCTCATGTCAACGTGGGTACAAGGGAGTCTGGCGGGGCGACGGCATCATGCAAACCACCTGCCCATGTGGAGCACAGATCACCGGACATGTGAAAAACGGTTCCATGAGGATCGTGGGGCCTAGGACCTGTAGTAACACGTGGCATGGAACATTCCCCATTAACGCGTACACCACGGGCCCCTGCACGCCCTCCCCGGCGCCAAATTATTCTAGGGCGCTGTGGCGGGTGGCTGCTGAGGAGTACGTGGAGGTTACGCGGGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCGTGTCAGGTTCCGGCCCCCGAATTCTTCACAGAAGTGGATGGGGTGCGGTTGCACAGGTACGCTCCAGCGTGCAAACCCCTCCTACGGGAGGAGGTCACATTCCTGGTCGGGCTCAATCAATACCTGGTTGGGTCACAGCTCCCATGCGAGCCCGAACCGGACGTAGCAGTGCTCACTTCCATGCTCACCGACCCCTCCCACATTACGGCGGAGACGGCTAAGCGTAGGCTGGCCAGGGGATCTCCCCCCTCCTTGGCCAGCTCATCAGCTATCCAGCTGTCTGCGCCTTCCTTGAAGGCAACATGCACTACCCGTCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCCTGTGGCGGCAGGAGATGGGCGGGAACATCACCCGCGTGGAGTCAGAAAATAAGGTAGTAATTTTGGACTCTTTCGAGCCGCTCCAAGCGGAGGAGGATGAGAGGGAAGTATCCGTTCCGGCGGAGATCCTGCGGAGGTCCAGGAAATTCCCTCGAGCGATGCCCATATGGGCACGCCCGGATTACAACCCTCCACTGTTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCAGTGGTACACGGGTGTCCATTGCCGCCTGCCAAGGCCCCTCCGATACCACCTCCACGGAGGAAGAGGACGGTTGTCCTGTCAGAATCTACCGTGTCTTCTGCCTTGGCGGAGCTCGCCACAAAGACCTTCGGCAGCTCCGAATCGTCGGCCGTCGACAGCGGCACGGCAACGGCCTCTCCTGACCAGCCCTCCGACGACGGCGACGCGGGATCCGACGTTGAGTCGTACTCCTCCATGCCCCCCCTTGAGGGGGAGCCGGGGGATCCCGATCTCAGCGACGGGTCTTGGTCTACCGTAAGCGAGGAGGCTAGTGAGGACGTCGTCTGCTGCTCGATGTCGTACACATGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAACCAAGCTGCCCATCAATGCACTGAGCAACTCTTTGGTCCGTCACCACAACTTGGTCTATGCTACAACATCTCGCAGCGCAAGCCTGCGGCAGAAGAAGGTCACCTTTGACAGACTGCAGGTCCTGGACGACCACTACCGGGACGTGCTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAACTTCTATCCGTGGAGGAAGCCTGTAAGCTGACGCCCCCACATTCGGCCAGATCTAAATTTGGCTATGGGGCAAAGGACGTCCGGAACCTATCCAGCAAGGCCGTTAACCACATCCGCTCCGTGTGGAAGGACTTGCTGGAAGACACTGAGACACCAATtGACACTACCATCATGGCCAAGAACGAGGTTTTCTGCGTTCAGCCTGAGAAGGGGGGTCGTAAGCCAGCTCGTGTCATCGTGTTCCCCGACCTGGGCGTGCGCGTGTGCGAGAAGATGGCCCTGTACGACGTGGTTAGCAAGCTCCCCCTGGCCGTGATGGGAAGCTCCTACGGATTCCAATACTCACCAGGACAGCGGGTTGAATTCCTCGTGCAAGCGTGGAAGTCCAAGAAGACCCCGATGGGGTTCTCGTATGATACCCGCTGTTTTGACTCCACAGTCACTGAGAGCGACATCCGTACGGAGGAGGCAATTTACCAATGTTGTGACCTGGACCCCCAAGCCCGCGTGGCCATCAAGTCCCTCACTGAGAGGCTTTATGTTGGGGGCCCTCTTACCAATTCAAGGGGGGAAAACTGCGGCTACCGCAGGTGCCGCGCGAGCGGCGTACTGACAACTAGCTGTGGTAACACCCTCACTTGCTACATCAAGGCCCGGGCAGCCTGTCGAGCCGCAGGGCTCCAGGACTGCACCATGCTCGTGTGTGGCGACGACTTAGTCGTTATCTGTGAAAGTGCGGGGGTCCAGGAGGACGCGGCGAGCCTGAGAGCCTTCACGGAGGCTATGACCAGGTACTCCGCCCCCCCCGGGGACCCCCCACAACCAGAATACGACTTGGAGCTTATAACATCATGCTCCTCCAACGTGTCAGTCGCCCACGACGGCGCTGGAAAGAGGGTCTACTACCTTACCCGTGACCCTACAACCCCCCTCGCGAGAGCCGCGTGGGAGACAGCAAGACACACTCCAGTCAATTCCTGGCTAGGCAACATAATCATGTTTGCCCCCACACTGTGGGCGAGGATGATACTGATGACCCATTTCTTTAGCGTCCTCATAGCCAGGGATCAGCTTGAACAGGCTCTTAACTGTGAGATCTACGGAGCCTGCTACTCCATAGAACCACTGGATCTACCTCCAATCATCAAAGACTCCATGGCCTCAGCGCATTTTCACTCCACAGTTACTCTCCAGGTGAAATCAATAGGGTGGCCGCATGCCTCAGAAAACTTGGGGTCCCGCCCTTGCGAGCTTGGAGACACCGGGCCCGGAGCGTCCGCGCTAGGCTTCTGTCCAGAGGAGGCAGGGCTGCCATATGTGGCAAGTACCTCTTCAACTGGGCAGTAAGAACAAAGCTCAAACTCACTCCAATAGCGGCCGCTGGCCGGCTGGAGTTGTCCGGTTGGTTCACGGCTGGCTACAGCGGGGGAGACATTTATCACAGCGTGTCTCATGCCCGGCCCCGCTGGTTCTGGTTTTGCCTACTCCTGCTCGCTGCAGGGGTAGGCATCTACCTCGTCCCCAACCGATGAAGGTTGGGGTAAACACTCCGGCCTCTTAAGCCATTTCCTGTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTCTTTCCTTTCCTTCTTTTTTTCCTTTCTTTTTCCCTTCTTTAATGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCtTGACTGCAGAGAGTGCTGATACTGGCCTCTCTGCAGA TCAaGTBB7/H77NS5B: [SEQ ID NO: 6]GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTCCACCATATTGCCGTGCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTGGACCAGGACCTCGTCGGCTGGCAAGCGCCCCCCGGGGCGCGTTCCTGGACACCATGCACCTGCGGCAGCTCGGACCTTTACTTGGTCACGAGGCATGCCGATGTCATTCCGGTGCGCCGGCGGGGCGACAGCAGGGGGAGCCTACTCTCCCCCAGGCCCGTCTCCTACTTGAAGGGCTCTTCGGGCGGTCCACTGCTCTGCCCCTCGGGGCACGCTGTGGGCATCTTTCGGGCTGCCGTGTGCACCCGAGGGGTTGCGAAGGCGGTGGACTTTGTACCCGTCGAGTCTATGGAAACCACTATGCGGTCCCCGGTCTTCACGGACAACTCGTCCCCTCCGGCCGTACCGCAGACATTCCAGGTGGCCCATCTACACGCCCCTACTGGTAGCGGCAAGAGCACTAAGGTGCCGGCTGCGTATGCAGCCCAAGGGTATAAGGTGCTTGTCCTGAACCCGTCCGTCGCCGCCACCCTAGGTTTCGGGGCGTATATGTCTAAGGCACATGGTATCGACCCTAACATCAGAACCGGGGTAAGGACCATCACCACGGGTGCCCCCATCACGTACTCCACCTATGGCAAGTTTCTTGCCGACGGTGGTTGCTCTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAACTGACTCGACCACTATCGTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGACTCGTCGTGCTCGCCACCGCTACGCCTCCGGGATCGGTCACCGTGCCACATCCAAACATCGAGGAGGTGGCTCTGTCCAGCACTGGAGAAATCCCCTTTTATGGCAAAGCCATCCCCATCGAGACCATCAAGGGGGGGAGGCACCTCATTTTCTGCCATTCCAAGAAGAAATGTGATGAGCTCGCCGCGAAGCTGTCCGGCCTCGGACTCAATGCTGTAGCATATTACCGGGGCCTTGATGTATCCGTCATACCAACTAGCGGAGACGTCATTGTCGTAGCAACGGACGCTCTAATGACGGGCTTTACCGGCGATTTCGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCCTGGACCCGACCTTCACCATTGAGACGACGACCGTGCCACAAGACGCGGTGTCACGCTCGCAGCGGCGAGGCAGGACTGGTAGGGGCAGGATGGGCATTTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCCTCGGTTCTGTGCGAGTGCTATGACGCGGGCTGTGCTTGGTACGAGCTCACGCCCGCCGAGACCTCAGTTAGGTTGCGGGCTTACCTAAACACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGAGCGTCTTTACAGGCCTCACCCACATAGACGCCCATTTCTTGTCCCAGACTAAGCAGGCAGGAGACAACTTCCCCTACCTGGTAGCATACCAGGCTACGGTGTGCGCCAGGGCTCAGGCTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTAAAGCCTACGCTGCACGGGCCAACGCCCCTGCTGTATAGGCTGGGAGCCGTTCAAAACGAGGTTACTACCACACACCCCATAACCAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACGAGCACCTGGGTGCTGGTAGGCGGAGTCCTAGCAGCTCTGGCCGCGTATTGCCTGACAACAGGCAGCGTGGTCATTGTGGGCAGGATCATCTTGTCCGGAAAGCCGGCCATCATTCCCGACAGGGAAGTCCTTTACCGGGAGTTCGATGAGATGGAAGAGTGCGCCTCACACCTCCCTTACATCGAACAGGGAATGCAGCTCGCCGAACAATTCAAACAGAAGGCAATCGGGTTGCTGCAAACAGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAATCCAAGTGGCGGACCCTCGAAGCCTTCTGGGCGAAGCATATGTGGAATTCATCAGCGGGATACAATATTTAGCAGGCTTGTCCACTCTGCCTGGCAACCCCGCGATAGCATCACTGATGGCATTCACAGCCTCTATCACCAGCCCGCTCACCACCCAACATACCCTCCTGTTTAACATCCTGGGGGGATGGGTGGCCGCCCAACTTGCTCCTCCCAGCGCTGCTTCTGCTTTCGTAGGCGCCGGCATCGCTGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTTGTGGATATTTTGGCAGGTTATGGAGCAGGGGTGGCAGGCGCGCTCGTGGCCTTTAAGGTCATGAGCGGCGAGATGCCCTCCACCGAGGACCTGGTTAACCTACTCCCTGCTATCCTCTCCCCTGGCGCCCTAGTCGTCGGGGTCGTGTGCGCAGCGATACTGCGTCGGCACGTGGGCCCAGGGGAGGGGGCTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCCCACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCCTCTCTAGTCTTACCATCACTCAGCTGCTGAAGAGGCTTCACCAGTGGATCAACGAGGACTGCTCCACGCCATGCTCCGGCTCGTGGCTAAGAGATGTTTGGGATTGGATATGCACGGTGTTGACTGATTTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCGATTGCCGGGAGTCCCCTTCTTCTCATGTCAACGTGGGTACAAGGGAGTCTGGCGGGGCGACGGCATCATGCAAACCACCTGCCCATGTGGAGCACAGATCACCGGACATGTGAAAAACGGTTCCATGAGGATCGTGGGGCCTAGGACCTGTAGTAACACGTGGCATGGAACATTCCCCATTAACGCGTACACCACGGGCCCCTGCACGCCCTCCCCGGCGCCAAATTATTCTAGGGCGCTGTGGCGGGTGGCTGCTGAGGAGTACGTGGAGGTTACGCGGGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCGTGTCAGGTTCCGGCCCCCGAATTCTTCACAGAAGTGGATGGGGTGCGGTTGCACAGGTACGCTCCAGCGTGCAAACCCCTCCTACGGGAGGAGGTCACATTCCTGGTCGGGCTCAATCAATACCTGGTTGGGTCACAGCTCCCATGCGAGCCCGAACCGGACGTAGCAGTGCTCACTTCCATGCTCACCGACCCCTCCCACATTACGGCGGAGACGGCTAAGCGTAGGCTGGCCAGGGGATCTCCCCCCTCCTTGGCCAGCTCATCAGCTATCCAGCTGTCTGCGCCTTCCTTGAAGGCAACATGCACTACCCGTCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCCTGTGGCGGCAGGAGATGGGCGGGAACATCACCCGCGTGGAGTCAGAAAATAAGGTAGTAATTTTGGACTCTTTCGAGCCGCTCCAAGCGGAGGAGGATGAGAGGGAAGTATCCGTTCCGGCGGAGATCCTGCGGAGGTCCAGGAAATTCCCTCGAGCGATGCCCATATGGGCACGCCCGGATTACAACCCTCCACTGTTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCAGTGGTACACGGGTGTCCATTGCCGCCTGCCAAGGCCCCTCCGATACCACCTCCACGGAGGAAGAGGACGGTTGTCCTGTCAGAATCTACCGTGTCTTCTGCCTTGGCGGAGCTCGCCACAAAGACCTTCGGCAGCTCCGAATCGTCGGCCGTCGACAGCGGCACGGCAACGGCCTCTCCTGACCAGCCCTCCGACGACGGCGACGCGGGATCCGACGTTGAGTCGTAGTCCTCCATGCCCCCCCTTGAGGGGGAGCCGGGGGATCCCGATCTCAGCGACGGGTCTTGGTCTACCGTAAGCGAGGAGGCTAGTGAGGACGTCGTCTGCTGCTCGATGTCCTACACATGGACAGGCGCCCTGATCACCCCGTGCGCTGCGGAAGAACAAAAACTGCCCATCAACGCACTGAGCAACTCGTTGCTACGCCATCACAATCTGGTGTATTCCACCACTTCACGCAGTGCTTGCCAAAGGCAGAAGAAAGTCACATTTGACAGACTGCAAGTTCTGGACAGCCATTACCAGGACGTGCTCAAGGAGGTCAAAGCAGCGGCGTCAAAAGTGAAGGCTAACTTGCTATCCGTAGAGGAAGCTTGCAGCCTGACGCCCCCACATTCAGCCAAATCCAAGTTTGGCTATGGGGCAAAAGACGTCCGTTGCCATGCCAGAAAGGCCGTAGCCCACATCAACTCCGTGTGGAAAGACCTTCTGGAAGACAGTGTAACACCAATAGACACTACCATCATGGCCAAGAACGAGGTTTTCTGCGTTCAGCCTGAGAAGGGGGGTCGTAAGCCAGCTCGTCTCATCGTGTTCCCCGACCTGGGCGTGCGCGTGTGCGAGAAGATGGCCCTGTACGACGTGGTTAGCAAGCTCCCCCTGGCCGTGATGGGAAGCTCCTACGGATTCCAATACTCACCAGGACAGCGGGTTGAATTCCTCGTGCAAGCGTGGAAGTCCAAGAAGACCCCGATGGGGTTCTCGTATGATACCCGCTGTTTTGACTCCACAGTCACTGAGAGCGACATCCGTACGGAGGAGGCAATTTACCAATGTTGTGACCTGGACCCCCAAGCCCGCGTGGCCATCAAGTCCCTCACTGAGAGGCTTTATGTTGGGGGCCCTCTTACCAATTCAAGGGGGGAAAACTGCGGCTACCGCAGGTGCCGCGCGAGCGGCGTACTGACAACTAGCTGTGGTAACACCCTCACTTGCTACATCAAGGCCCGGGCAGCCTGTCGAGCCGCAGGGCTCCAGGACTGCACCATGCTCGTGTGTGGCGACGACTTAGTCGTTATCTGTGAAAGTGCGGGGGTCCAGGAGGACGCGGCGAGCCTGAGAGCCTTCACGGAGGCTATGACCAGGTAGTCCtCCCCCCCCGGGGACCCCCCACAACCAGAATACGACTTGGAGCTTATAACATCATGCTCGTCCAACGTGTCAGTCGCCCACGACGGCGCTGGAAAGAGGGTCTACTACCTTACCCGTGACCCTACAACCCCCCTCGCGAGAGCCGCGTGGGAGACAGCAAGACACACTCCAGTCAATTCCTGGCTAGGCAACATAATCATGTTTGCCCCCACACTGTGGGCGAGGATGATACTGATGACCCATTTCTTTAGCGTCCTCATAGCCAGGGATCAGCTTGAACAGGCTCTTAACTGTGAGATCTACGGAGCCTGCTACTCCATAGAACCACTGGATCTACCTCCAATCATTCAAAGACTCCATGGCCTCAGCGCATTTTCACTCCACAGTTACTCTCCAGGTGAAATCAATAGGGTGGCCGCATGCCTCAGAAAACTTGGGGTCCCGCCCTTGCGAGCTTGGAGACACCGGGCCCGGAGCGTCCGCGCTAGGCTTCTGTCCAGAGGAGGCAGGGCTGCCATATGTGGCAAGTACCTCTTCAACTGGGCAGTAAGAACAAAGCTCAAACTCACTCCAATAGCGGCCGCTGGCCGGCTGGACTTGTCCGGTTGGTTCACGGCTGGCTACAGCGGGGGAGACATTTATCACAGCGTGTCTCATGCCCGGCCCCGCTGGTTCTGGTTTTGCGTACTCCTGCTCGCTGCAGGGGTAGGCATCTACCTCCTCCCCAACCGATGAAGGTTtacGTAAACACTCCAGGCCAATAGGCCATCCTGTTTTTTTCCCTTTTTTTTTTTCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTCCTTTTTTTTTCCTCTTTTTTTCCTTTTCTTTCCTTTGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCTTGAGTGCAGAGAGTGCTGATACTGGCCT CTCTGCAGATCAAGTHCV 1a replicon: [SEQ ID NO: 7]GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGGTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCGTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGAGTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCGTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTGGACCAAGACCTTGTGGGCTGGCCCGCTCCTCAAGGTTCCCGCTCATTGACACCCTGTACCTGCGGCTCCTCGGACCTTTACCTGGTCACGAGGCACGCCGATGTCATTCCCGTGCGCCGGCGAGGTGATAGCAGGGGTAGCCTGCTTTCGCCCCGGCCCATTTCCTACTTGAAAGGCTCCTCGGGGGGTCCGCTGTTGTGCCCCGCGGGACACGCCGTGGGCCTATTCAGGGCCGCGGTGTGCACCCGTGGAGTGGCTAAAGCGGTGGACTTTATCCCTGTGGAGAACCTAGGGACAACCATGAGATCCCCGGTGTTCACGGACAACTCCTCTCCACCAGCAGTGCCCCAGAGCTTCCAGGTGGCCCACCTGCATGCTCCCACCGGCAGCGGTAAGAGCACCAAGGTCCCGGCTGCGTACGCAGCCCAGGGCTACAAGGTGTTGGTGCTCAACCCCTCTGTTGCTGCAACGCTGGGCTTTGGTGCTTACATGTCCAAGGCCCATGGGGTTGATCCTAATATCAGGACCGGGGTGAGAACAATTACCACTGGCAGCCCCATCACGTACTCCACCTACGGCAAGTTCCTTGCCGACGGCGGGTGCTCAGGAGGTGCTTATGACATAATAATTTGTGACGAGTGCCACTCCACGGATGCCACATCCATCTTGGGCATCGGCACTGTCCTTGACCAAGCAGAGACTGCGGGGGCGAGACTGGTTGTGCTCGCCACTGCTACCCCTCCGGGCTCCGTCACTGTGcCCCATCCTAACATCGAGGAGGTTGCTCTGTCCACCACCGGAGAGATCCCCTTTTACGGCAAGGCTATCCCCCTCGAGGTGATCAAGGGGGGAAGACATCTCATCTTCTGCCACTCAAAGAAGAAGTGCGACGAGCTCGCCGCGAAGCTGGTCGCATTGGGCATCAATGCCGTGGCCTACTACCGCGGTCTTGACGTGTCTGTCATCCCGACCAGCGGCGATGTTGTCGTCGTGTCGACCGATGCTCTCATGACTGGCTTTACCGGCGACTTCGACTGTGTGATAGACTGCAACACGTGTGTCACTCAGACAGTCGATTTCAGCCTTGACCCTACCTTTACCATTGAGACAACCACGCTCCCCCAGGATGCTGTGTCCAGGACTCAACGCCGGGGCAGGACTGGCAGGGGGAAGCCAGGCATCTATAGATTTGTGGCACCGGGGGAGCGCCCCTCCGGCATGTTCGACTCGTCCGTCCTCTGTGAGTGCTATGACGCGGGCTGTGCTTGGTATGAGCTCACGCCCGCCGAGACTACAGTTAGGCTACGAGCGTACATGAACACCCCGGGGCTTCCCGTGTGCCAGGACCATCTTGAATTTTGGGAGGGCGTCTTTACGGGCCTCACTCATATAGATGCCCACTTTTTATCCCAGACAAAGCAGAGTGGGGAGAACTTTCCTTACCTGGTAGCGTACCAAGCCACCGTGTGCGCTAGGGCTCAAGCCCCTCCCCCATCGTGGGACCAGATGTGGGAGTGTTTGATCCGCCTTAAACCCACCCTCCATGGGCCAACACCCCTGCTATACAGACTGGGCGCTGTTCAGAATGAAGTCACCCTGACGCACCCAATCACCAAATACATCATGACATGCATGTCGGCCGACCTGGAGGTCGTCACGAGCACCTGGGTGCTCGTTGGCGGCGTCCTGGCTGCTCTGGCCGCGTATTGCCTGTCAACAGGCTGCGTGGTCATAGTGGGCAGGATCGTCTTGTCCGGGAAGCCGGCAATTATACCTGACAGGGAGGTTCTCTACCAGGAGTTCGATGAGATGGAAGAGTGCTCTCAGCACTTACCGTACATCGAGCAAGGGATGATGCTCGCTGAGCAGTTCAAGCAGAAGGCCCTCGGCCTCCTGCAGACCGCGTCCCGCCATGCAGAGGTTATCACCCCTGCTGTCCAGACCAACTGGCAGAAACTCGAGGTCTTTTGGGCGAAGCACATGTGGAATTTCATCAGTGGGATACAATACTTGGCGGGCCTGTCAACGCTGCCTGGTAACCCCGCCATTGCTTCATTGATGGGCTTTTACAGCTGCCGTCACCAGCCCACTAACCACTGGCCAAACCCTCCTCTTCAACATATTGGGGGGGTGGGTGGCTGCCCAGCTCGCCGCCCCCGGTGCCGCTACTGCCTTTGTGGGTGCTGGCCTAGCTGGCGCCGCCATCGGCAGCGTTGGACTGGGGAAGGTCCTCGTGGACATTCTTGCAGGGTATGGCGCGGGCGTGGCGGGAGCTCTTGTAGCATTCAAGATCATGAGCGGTGAGGTCCCCTCCACGGAGGACCTGGTCAATCTGGTGCCCGCCATCCTCTCGCCTGGAGCCCTTGTAGTCGGTGTGGTCTGCGCAGCAATACTGCGCCGGCACGTTGGCCCGGGCGAGGGGGCAGTGCAATGGATGAACCGGCTAATAGCCTTCGCCTCCCGGGGGAACCATGTTTCCCCCACGCACTACGTGCCGGAGAGCGATGCAGCCGCCCGCGTCACTGCCATACTCAGCAGCCTCACTGTAACCCAGCTCCTGAGGCGACTGCATCAGTGGATAAGCTCGGAGTGTACCACTCCATGCTCCGGTTCCTGGCTAAGGGACATGTGGGACTGGATATGCGtGGTGCTGAGCGACTTTAAGACCTGGCTGAAAGCCAAGCTCATGCCACAACTGCCTGGGATTCCCTTTGTGTCCTGCCAGCGCGGGTATAGGGGGGTCTGGCGAGGAGACGGCATTATGCACACTCGCTGCCACTGTGGAGCTGAGATCACTGGACATGTCAAAAACGGGACGATGAGGATCGTCGGTCCTAGGACCTGCAGGAACATGTGGAGTGGGACGTTCCCCATTAACGCCTACACCACGGGCCCCTGTACTCCCCTTCCTGCGCCGAACTATAAGTTCGCGCTGTGGAGGGTGTCTGCAGAGGAATACGTGGAGATAAGGCGGGTGGGGGACTTCCACTACGTATCGGGTATGAGTACTGACAATCTAAATGCCCGTGCCAGATCCCATCGCCCGAATTcTTCACAGAATTGGACGGGGTGCGCCTACACAGGTTTGCGCCCCCTTGCAAGCCCTTGCTGCGGGAGGAGGTATCATTCAGAGTAGGACTCCACGAGTACCCGGTGGGGTCGCAATTACCTTGCGAGCCCGAACCGGACGTAGCCGTGTTGACGTCCATGCTCAGTGATCCCTCCCATATAACAGCAGAGGCGGCCGGGAGAAGGTTGGCGAGAGGGTCACCCCCTTCTATGGCCAGCTCCTCGGCTAtCCAGCTGTCCGGTCCATCTCTCAAGGCAACTTGCACCGCCAACCATGACTCCCCTGACGCCGAGCTCATAGAGGCTAACCTCCTGTGGAGGCAGGAGATGGGCGGCAACATCACCAGGGTTGAGTCAGAGAACAAAGTGGTGATTCTGGACTCCTTCGATCCGCTTGTGGCAGAGGAGGATGAGCGGGAGGTCTCCGTACCTGCAGAAATTCTGCGGAAGTCTCGGAGATTCGCCCGGGCCCTGCCCGTCTGGGCGCGGCCGGACTACAACCCCCCGCTAGTAGAGACGTGGAAAAAGCCTGACTACGAACCACCTGTGGTCCATGGCTGCCCGCTACCACCTCCACGGTCCCCTCCTGTGCCTCCGCCTCGGAAAAAGCGTACGGTGGTCCTCACCGAATCAACCCTATCTACTGCCTTGGCCGAGCTTGCCACCAAAAGTTTTGGCAGCTCCTCAACTTCCGGCATTACGGGCGACAATACGACAACATCCTCTGAGCCCGCCCCTTCTGGCTGCCCCCCCGACTCCGACGTTGAGTCCTATTCTTCCATGCCCCCCCTGGAGGGGGAGCCTGGGGATCCGGATGTCAGCGACGGGTCATGGTCGACGGTCAGTAGTGGGGCCGACACGGAAGATGTCGTGTGCTGCTCAATGTCTTATTCCTGGACAGGCGCACTCGTCACCCCGTGCGCTGCGGAAGAACAAAAACTGCCCATCAACGCACTGAGCAACTCGTTGCTACGCCATCACAATCTGGTGTATTCCACCACTTCACGCAGTGCTTGCCAAAGGCAGAAGAAAGTCACATTTGACAGACTGCAAGTTCTGGACAGCCATTACCAGGACGTGCTCAAGGAGGTCAAAGCAGCGGCGTCAAAAGTGAAGGCTAACTTGCTATCCGTAGAGGAAGCTTGCAGCCTGACGCCCCCACATTCAGCCAAATCCAAGTTTGGCTATGGGGCAAAAGACGTCCGTTGCCATGCCAGAAAGGCCGTAGCCCACATCAACTCCGTGTGGAAAGACCTTCTGGAAGACAGTGTAACACCAATtGACACTACCATCATGGCCAAGAACGAGGTTTTCTGCGTTCAGCCTGAGAAGGGGGGTCGTAAGCCAGCTCGTCTCATCGTGTTCCCCGACCTGGGCGTGCGCGTGTGCGAGAAGATGGCCCTGTACGACGTGaTTAGCAAGCTCCCCGTGGCCGTGATGGGAAGCTCCTACGGATTCCAATACTCACCAGGACAGCGGGTTGAATTCCTCGTGCAAGCGTGGAAGTCCAAGAAGACCCCGATGGGGTTCTCGTATGATACCCGCTGTTTTGACTCCACAGTCACTGAGAGCGACATCCGTACGGAGGAGGCAATTTACCAATGTTGTGACCTGGACCCCCAAGCCCGCGTGGCCATCAAGTCCCTCACTGAGAGGCTTTATGTTGGGGGCCCTCTTACCAATTCAAGGGGGGAAAACTGCGGCTACCGCAGGTGCCGCGCGAGCGGCGTACTGACAACTAGCTGTGGTAACACCCTCACTTGCTACATCAAGGCCCGGGCAGCCTGTCGAGCCGCAGGGCTCCAGGACTGCACCATGCTCGTGTGTGGaGACGACTTAGTCGTTATCTGTGAAAGTGCGGGGGTCCAGGAGGACGCGGCGAGCCTGAGAGCCTTCACGGAGGCTATGACCAGGTACTCCGCCCCCCCCGGGGACCCCCCACAACCAGAATACGACTTGGAGCTTATAACATCATGCTCCTCCAACGTGTCAGTCGCCCACGACGGCGCTGGAAAGAGGGTCTACTACCTTACCCGTGACCCTACAACCCCCCTCGAGAGAGCCGCGTGGGAGACAGCAAGACACACTCCAGTCAATTCCTGGCTAGGCAACATAATCATGTTTGCCCCCACACTGTGGGCGAGGATGATACTGATGACCCATTTCTTTAGCGTCCTCATAGCCAGGGATCAGCTTGAACAGGCTCTTAACTGTGAGATCTACGGAGCCTGCTACTCCATAGAACCACTaGATCTACCTCCAATCATTCAAAGACTCCATGGCCTCAGCGCATTTTCACTCCACAGTTACTCTCCAGGTGAAATCAATAGGGTGGCCGCATGCGTCAGAAAACTTGGGGTCCCGCCCTTGCGAGCTTGGAGACACCGGGCCCGGAGCGTCCGCGCTAGGCTTCTGTCCAGAGGAGGCAGGGCTGCCATATGTGGCAAGTACCTCTTCAACTGGGCAGTAAGAACAAAGCTCAAACTCACTCCAATAGCGGCCGCTGGCCGGCTGGACTTGTCCGGTTGGTTCACGGCTGGCTACAGCGGGGGAGACATTTATCACAGCGTGTCTCATGCCCGGCCCCGCTGGTTCTGGTTTTGCCTACTCCTGCTCGCTGCAGGGGTAGGCATCTACCTCCTCCCCAACCGATGAAGGTTGGGGTAAACACTCCGGCCTCTTAAGCCATTTCCTGTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTCTTTCCTTTCCTTCTTTTTTTCCTTTCTTTTTCCCTTCTTTAATGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCtTGACTGCAGAGAGTGCTGATACTGGCCTCTGTGC AGATCAaGT (B)Sequences from HCV J4 Replicons J4 M/S: [SEQ ID NO: 8]GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGGTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCGTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGAGTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTfGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTAGACGTGGACCTCGTCGGCTGGCAGGCGCCCCCCGGGGCGCGCTCCATGACACCATGCAGCTGTGGCAGCTCGGACCTTTACTTGGTCACGAGACATGCTGATGTCATTCCGGTGCGCCGGCGAGGCGACAGCAGGGGAAGTCTACTCTCCCCCAGGCCCGTCTCCTACCTGAAAGGCTCCTCGGGTGGTCCATTGCTTTGCCCTTCGGGGCACGTCGTGGGCGTCTTCCGGGCTGCTGTGTGCACCCGGGGGGTCGCGAAGGCGGTGGACTTCATACCCGTTGAGTCTATGGAAACTACCATGCGGTCTCCGGTCTTCACAGACAACTCAACCCCCCCGGCTGTACCGCAGACATTCCAAGTGGCACATCTGCACGCTCCTACTGGCAGCGGCAAGAGCACCAAAGTGCCGGCTGCGTATGCAGCCCAAGGGTACAAGGTGCTCGTCCTGAACCCGTCCGTTGCCGCCACCTTAGGGTTTGGGGCGTATATGTCCAAGGCACACGGTATCGACCCTAACATCAGAACTGGGGTAAGGACCATTACCACGGGCGGCTCCATTACGTACTCCACCTATGGCAAGTTCCTTGCCGACGGTGGCTGTTCTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAACTGACTCGACTACCATCTTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGGCTCGTCGTGCTCGCCACCGCTACACCTCCGGGATCGGTTACCGTGCCACACCCCAATATCGAGGAAATAGGCCTGTCCAACAATGGAGAGATCCCCTTCTATGGCAAAGCCATCCCCATTGAGGCCATCAAGGGGGGGAGGCATCTCATTTTCTGCCATTCCAAGAAGAAATGTGACGAGCTCGCCGCAAAGCTGACAGGCCTCGGACTGAACGCTGTAGCATATTACCGGGGCCTTGATGTGTCCGTCATACCGCCTATCGGAGACGTCGTTGTCGTGGCAACAGACGCTCTAATGACGGGTTTCACCGGCGATTTTGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCTTGGATCCCACCTTCACCATTGAGACGACGACCGTGCCCCAAGACGCGGTGTCGCGCTCGCAACGGCGAGGTAGAACTGGCAGGGGTAGGAGTGGCATCTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCTTCGGTCCTGTGTGAGTGCTATGACGCGGGCTGTGCTTGGTATGAGCTCACGCCCGCTGAGACCTCGGTTAGGTTGCGGGCTTACGTAAATACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGAGCGTCTTCACAGGCCTCACCCACATAGATGCCCACTTCCTGTCCCAGACTAAACAGGCAGGAGACAACTTTCCTTACCTGGTGGCATATCAAGCTACAGTGTGCGCCAGGGCTCAAGCTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTGAAACCTACACTGCACGGGCCAACACCCCTGCTGTATAGGCTAGGAGCCGTCCAAAATGAGGTCATCGTCACACACCCCATAACTAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACTAGCACCTGGGTGCTGGTAGGCGGAGTCCTTGCAGCTTTGGCCGCATACTGCCTGACGACAGGCAGTGTGGTCATTGTGGGCAGGATCATCTTGTCCGGGAAGCCAGCTGTCGTTCCCGACAGGGAAGTCCTCTACCAGGAGTTCGATGAGATGGAAGAGTGTGCCTCACAACTTCCTTACATCGAGCAGGGAATGCAGCTCGCCGAGCAATTCAAGCAAAAGGCGGTCGGGTTGTTGCAAACGGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAGTCCAAGTGGCGAGCCCTTGAGACCTTCTGGGCGAAGCACATGTGGAATTTCATCAGCGGAATACAGTACCTAGCAGGCTTATCCACTCTGCCTGGAAACCCCGCGATAGCATCATTGATGGCATTTACAGCTTCTATCACTAGCCCGCTCACCACCCAAAACACCCTCCTGTTTAACATCTTGGGGGGATGGGTGGCTGCCCAACTCGCTCCTCCCAGCGCTGCGTCAGCTTTCGTGGGCGCCGGCATCGCCGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTCGTGGACATCTTGGCGGGCTATGGGGCAGGGGTAGCCGGCGCACTCGTGGCCTTTAAGGTCATGAGCGGCGAGGTGCCCTCCACCGAGGACCTGGTCAACTTACTCCGTGCCATCCTCTCTCCTGGTGCCCTGGTCGTCGGGGTCGTGTGCGCAGCAATACTGCGTCGGCACGTGGGCCCGGGAGAGGGGGCTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCCTACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCCTCTCTAGCCTTACCATCACTCAACTGCTGAAGCGGCTCCACCAGTGGATTAATGAGGACTGCTCTACGCCATGCTCCGGCTCGTGGCTAAGGGATGTTTGGGATTGGATATGCACGGTGTTGACTGACTTCAAGACCTGGCTCCAGTCCAAACTCCTGCCGCGGTTACCGGGAGTCCCTTTCCTGTCATGCCAACGCGGGTACAAGGGAGTCTGGCGGGGGGACGGCATCATGCAAACCACCTGCCCATGCGGAGCACAGATCGCCGGACATGTCAAAAACGGTTCCATGAGGATCGTAGGGCCTAGAACCTGCAGCAACACGTGGCACGGAACGTTCCCCATCAACGCATACACCACGGGACCTTGCACACCCTCCCCGGCGCCCAACTATTCCAGGGCGCTATGGCGGGTGGGTGCTGAGGAGTACGTGGAGGTTACGCGTGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCATGCCAGGTTCCGGCCCCCGAATTCTTCACGGAGGTGGATGGAGTGCGGTTGCACAGGTACGCTCCGGCGTGCAAACCTCTTCTACGGGAGGACGTCACGTTCCAGGTCGGGCTCAACCAATACTTGGTCGGGTCGCAGCTCCCATGCGAGCCCGAACCGGACGTAACAGTGCTTACTTCCATGCTCACCGATCCCTCCCACATTACAGCAGAGACGGCTAAGCGTAGGCTGGCTAGAGGGTGTCCCCCCTCTTTAGCCAGCTCATCAGCTAtCCAGTTGTCTGCGCCTTCTTTGAAGGCGACATGCACTACCCACCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCTTGTGGCGGCAGGAGATGGGCGGAAACATCACTCGCGTGGAGTCAGAGAATAAGGTAGTAATTCTGGACTCTTTCGAACCGCTTTCACGCGGAGGGGGATGAGAGGGAGATATCCGTCGCGGCGGAGATCCTGCGAAAATCCAGGAAGUCCCCTCAGCGTTGCCCATATGGGCACGCCCGGACTACAATCCTCCACTGCTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCGGTGGTACACGGATGCCCATTGCCACCTACCAAGGCTCCTCCAATACCACCTCCACGGAGAAAGAGGACGGTTGTCCTGACAGAATCCAATGTGTCTTCTGCGTTGGCGGAGCTCGCCACTAAGACCTTCGGTAGCTCCGGATCGTCGGCCGTTGATAGCGGCACGGCGACCGCCCTTCCTGACGTGGCCTCCGACGACGGTGACAAAGGATCCGACGTTGAGTCGTACTCCTCCATGCCCCCCCTTGAAGGGGAGCCGGGGGACCCCGATCTCAGCGACGGGTCTTGGTCTACCGTGAGTGAGGAGGCTAGTGAGGATGTCGTCTGGTGCTCAATGTCCTATACGTGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAAGTAAGCTGCCCATCAACCCGTTGAGCAACTCTTTGCTGCGTCACCACAACATGGTCTACGCCACAACATCCCGCAGCGCAAGCCTCCGGCAGAAGAAGGTCACCTTTGACAGATTGCAAGTCCTGGATGATCATTACCGGGACGTACTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAGCTTCTATCTATAGAGGAGGCCTGCAAGCTGACGCCCCCACATTCGGCCAAATCCAAATTTGGCTATGGGGCAAAGGACGTCCGGAACCTATCCAGCAGGGCCGTTAACCACATCCGCTCCGTGTGGGAGGACTTGCTGGAAGACACTGAAACACCAATTGACACCACCATCATGGCAAAAAATGAGGTTTTCTGCGTCCAACCAGAGAAGGGGGGCCGCAAGCCAGCTCGCCTTATCGTATTCCCAGATTTGGGGGTTCGTGTGTGCGAGAAAATGGCCCTTTACGATGTGGTGTCCACCCTCCTCAGGCCGTGATGGGCTCTTCATACGGATTCCAATACTCTCCTGGACAGCGGGTCGAGTTCCTGGTGAATGCCTGGAAAGCGAAGAAATGCCCTATGGGCTTCGCATATGACACCCGCTGTTTTGACTCAACGGTCACTGAGAATGACATCCGTGTTGAGGAGTCAATCTACCAATGTTGTGACTTGGCCCCCGAAGCCAGACAGGCCATAAGGTCGCTCACAGAGCGGCTTTACATCGGGGGCCCCCTGACTAATTCTAAAGGGCAGAACTGCGGCTATCGCCGGTGCCGCGCGAGCGGTGTACTGACGACCAGCTGCGGTAATACCCTCACATGTTACTTGAAGGCCGCTGCGGCCTGTCGAGCTGCGAAGCTCCAGGACTGCACGATGCTCGTATGCGGAGACGACCTTGTCGTTATCTGTGAAAGCGCGGGGACCCAAGAGGACGAGGCGAGCCTACGGGCCTTCACGGAGGCTATGACTAGATACTCTGCCCCCCCTGGGGACCCGCCCAAACCAGAATACGACTTGGAGTTGATAACATCATGCTCCTCCAATGTGTCAGTCGCGCACGATGCATCTGGCAAAAGGGTGTACTATCTCACCCGTGACCCCACCACCCCCCTTGCGCGGGCTGCGTGGGAGACAGCTAGACACACTCCAGTCAATTCGTGGCTAGGCAACATCATCATGTATGCGCCCACCTTGTGGGCAAGGATGATCCTGATGACTCATTTCTTCTCCATCCTTCTAGCTCAGGAACAACTTGAAAAAGCCCTAGATTGTCAGATCTACGGGGCCTGTTACTCCATTGAGCCACTTGACCTACCTCAGATCATTCAACGACTCCATGGCCTTAGCGCATTTTCACTCCATAGTTACTCTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCGCCCTTGCGAGTGTGGAGACATCGGGCCAGAAGTGTCCGCGCTAGGCTACTGTCCCAGGGGGGGAGGGCTGCCACTTGTGGCAAGTACCTCTTCAACTGGGCAGTAAGGACCAAGCTCAAACTCACTCCAATCCCGGCTGCGTCCCAGTTGGATTTATCCAGCTGGTTCGTTGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCTGGTTCATGTGGTGCCTACTCGTACTTTCTGTAGGGGTAGGCATGTATCTACTCCCCAACCGATGAACGGGGACCTAAACACTCCAGGCCAATAGGCCATCCTGTTTTTTTCCCTTTTTTTTTTTCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTCCTTTTTTTTTCCTCTTTTTTTCCTTTTCTTTCCTTTGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCTTGACTGCAGAGAGTGCTGATACTGGCCT CTCTGCAGATCAAGTJ4 B/R1: [SEQ ID NO: 9]GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCGTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTGTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGGTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTGTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATGTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCGTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTGGACCAGGACCTCGTCGGCTGGCAAGCGCCCCCCGGGGCGCGTTCCTTGACACCATGCACCTGCGGCAGCTCGGACCTTTACTTGGTCACGAGGCATGCCGATGTCATTCCGGTGCGCCGGCGGGGCGACAGCAGGGGGAGCCTACTCTCCCCCAGGCCCGTCTCCTACTTGAAGGGCTCTTCGGGCGGTCCACTGCTGTGCCCCTCGGGGCACGCTGTGGGCATCTTTCGGGCTGCCGTGTGCACCCGAGGGGTTGCGAAGGCGGTGGACTTTGTACCCGTCGAGTCTATGGAAACCACTATGCGGTCCCCGGTCTTCACGGACAACTCGTCCCCTCCGGCCGTACCGCAGACATTCCAGGTGGCCCATCTACACGCCCCTACTGGTAGCGGCAAGAGCACTAAGGTGCCGGCTGCGTATGCAGCCCAAGGGTATAAGGTGCTTGTCGTGAACCCGTCCGTCGCCGCCACCCTAGGTTTCGGGGCGTATATGTCTAAGGCACATGGTATCGACCCTAACATCAGAACCGGGGTAAGGACCATCACCACGGGTGCCCCCATCACGTACTCCACCTATGGCAAGTTTCTTGCCGACGGTGGTTGCTCTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAACTGACTCGACCACTATCCTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGACTCGTCGTGCTCGCCACCGCTACGCCTCCGGGATCGGTCACCGTGCCACATCCAAACATCGAGGAGGTGGCTCTGTCCAGCACTGGAGAAATCCCCTTTTATGGCAAAGCCATCCCCATCGAGACCATCAAGGGGGGGAGGCACCTCATTTTCTGCCATTCCAAGAAGAAATGTGATGAGCTCGCCGCGAAGCTGTCCGGCCTCGGACTCAATGCTGTAGCATATTACCGGGGCCTTGATGTATCCGTCATACCAACTAGCGGAGACGTCATTGTCGTAGCAACGGACGCTCTAATGACGGGCTTTACCGGCGATTTCGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCCTGGACCCGACCTTCACCATTGAGACGACGACCGTGCCACAAGACGCGGTGTCACGCTCGCAGCGGCGAGGCAGGACTGGTAGGGGCAGGATGGGCATTTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCCTCGGTTCTGTGCGAGTGCTATGACGCGGGCTGTGCTTGGTACGAGCTCACGCCCGCCGAGACCTCAGTTAGGTTGCGGGCTTACCTAAACACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTGTGGGAGAGCGTCTTTACAGGCCTCACCCACATAGACGCCCATTTCTTGTCCCAGACTAAGCAGGCAGGAGACAACTTCCCCTACCTGGTAGCATACCAGGCTACGGTGTGCGCCAGGGCTCAGGCTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTAAAGCCTACGCTGCACGGGCCAACGCCCCTGCTGTATAGGCTGGGAGCCGTTCAAAACGAGGTTACTACCACACACCCCATAACCAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACGAGCACCTGGGTGCTGGTAGGCGGAGTCCTAGCAGCTCTGGCCGCGTATTGCCTGACAACAGGCAGCGTGGTCATTGTGGGCAGGATCATCTTGTCCGGAAAGCCGGCCATCATTCCCGACAGGGAAGTCCTTTACCGGGAGTTCGATGAGATGGAAGAGTGCGCCTCACACCTCCCTTACATCGAACAGGGAATGCAGCTCGCCGAACAATTCAAACAGAAGGCAATCGGGTTGCTGCAAACAGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAATCCAAGTGGCGGACCCTCGAAGCCTCTGGGCGAAGCATATGTGGAATTTCATCAGCGGGATACAATATTTAGCAGGCTTGTCCACTCTGCCTGGCAACCCCGCGATAGCATCACTGATGGCATTCACAGCCTCTATCACCAGCCCGCTCACCACCCAACATACCCTCCTGTTTAACATCCTGGGGGGATGGGTGGCCGCCCAACTTGCTCCTCCCAGCGCTGCTTCTGCTTTCGTAGGCGCCGGCATCGCTGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTTGTGGATATTTTGGCAGGTTATGGAGCAGGGGTGGCAGGCGCGCTCGTGGCCTTTAAGGTCATGAGCGGCGAGATGCCCTCCACCGAGGACCTGGTTAACCTACTCCCTGCTATCCTCTCCCCTGGCGCCCTAGTCGTCGGGGTCGTGTGCGCAGCGATACTGCGTCGGCACGTGGGCCCAGGGGAGGGGGGTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCCCACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCCTCTCTAGTCTTACCATCACTCAGCTGCTGAAGAGGCTTCACCAGTGGATCAACGAGGACTGCTCCACGCCATGCTCCGGCTCGTGGCTAAGAGATGTTTGGGATTGGATATGCACGGTGTTGACTGATTTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCGATTGCCGGGAGTCCCCTTCTTCTCATGTCAACGTGGGTACAAGGGAGTCTGGCGGGGCGACGGCATCATGCAAACCACCTGCCCATGTGGAGCACAGATCACCGGACATGTGAAAAACGGTTCCATGAGGATCGTGGGGCCTAGGACCTGTAGTAACACGTGGCATGGAACATTCCCCATTAACGCGTACACCACGGGCCCCTGCACGCCCTCCCCGGCGCCAAATTATTCTAGGGCGCTGTGGCGGGTGGCTGCTGAGGAGTACGTGGAGGTTACGCGGGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCGTGTCAGGTTCCGGCCCCCGAATTCTTCACGGAGGTGGATGGAGTGCGGTTGCACAGGTACGCTCCGGCGTGCAAACCTCTTCTACGGGAGGACGTCACGTTCCAGGTCGGGCTCAACCAATACTTGGTCGGGTCGCAGCTCCCATGCGAGCCCGAACCGGACGTAACAGTGCTTACTTCCATGCTCACCGATCCCTCCCACATTACAGCAGAGACGGCTAAGCGTAGGCTGGCTAGAGGGTCTCCCCCCTCTTTAGCCAGCTCATCAGCTAtCCAGTTGTCTGCGCCTTCTTTGAAGGCGACATGCACTACCCACCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCTTGTGGCGGCAGGAGATGGGCGGAAACATCACTCGCGTGGAGTCAGAGAATAAGGTAGTAATTCTGGACTCTTTCGAACCGCTTCACGCGGAGGGGGATGAGAGGGAGATATCCGTCGCGGCGGAGATCCTGCGAAAATCCAGGAAGTTCCCCTCAGCGTTGCCCATATGGGCACGCCCGGACTACAATCCTCCACTGCTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCGGTGGTACACGGATGCCCATTGCCACCTACCAAGGCTCCTCCAATACCACCTCCACGGAGAAAGAGGACGGTTGTCCTGACAGAATCCAATGTGTCTTCTGCGTTGGCGGAGCTCGCCACTAAGACCTTCGGTAGCTCCGGATCGTCGGCCGTTGATAGCGGCACGGCGACCGCCCTTCCTGACCTGGCCTCCGACGACGGTGACAAAGGATCCGACGTTGAGTCGTACTCGTCCATGCCCCCCCTTGAAGGGGAGCCGGGGGACCCCGATCTCAGCGACGGGTCTTGGTCTACCGTGAGTGAGGAGGCTAGTGAGGATGTCGTCTGCTGCTCAATGTCCTATACGTGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAAGTAAGCTGCCCATCAACCCGTTGAGCAACTCTTTGCTGCGTCACCACAACATGGTGTACGCCACAACATCCCGCAGCGCAAGCCTCCGGCAGAAGAAGGTCACCTTTGACAGATTGCAAGTCCTGGATGATCATTACCGGGACGTACTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAGCTTCTATCTATAGAGGAGGCGTGCAAGCTGACGCCCCCACATTCGGCCAAATCCAAATTTGGCTATGGGGCAAAGGACGTCCGGAACCTATCCAGCAGGGCCGTTAACCACATCCGCTCCGTGTGGGAGGACTTGCTGGAAGACACTGAAACACCAATTGACACCACCATCATGGCAAAAAGTGAGGTTTTCTGCGTCCAACCAGAGAAGGGAGGCCGCAAGCCAGCTCGCCTTATCGTATTCCCAGACCTGGGAGTTCGTGTATGCGAGAAGATGGCCCTTTACGACGTGGTCTCCACCCTTCGTCAGGCCGTGATGGGCTCCTCATACGGATTTCAATAGTCCCCCAAGCAGCGGGTCGAGTTCCTGGTGAATACCTGGAAATCAAAGAAATGCCCTATGGGCTTCTCATATGACACCCGCTGTTTTGACTCAACGGTCACTGAGAGTGACATTCGTGTTGAGGAGTCAATTTACCAATGTTGTGACTTGGCCCCCGAGGCCAGACAGGCCATAAGGTCGCTCACAGAGCGGCTTTACATCGGGGGTCCCGTGACTAACTCAAAAGGGCAGAACTGCGGTTATCGCCGGTGCCGCGCAAGTGGCGTGCTGACGACTAGCTGCGGTAATACCCTCACATGTTACTTGAAGGCCACTGCAGCGTGTCGAGCTGCAAAGCTCCAGGAGTGCACGATGCTCGTGAACGGAGACGACCTTGTCGTTATGTGTGAAAGCGCGGGAACCCAGGAGGATGCGGCGGCCCTACGAGCCTTCACGGAGGCTATGACTAGGTATTCCGCCCCCCCCGGGGATCCGCCCCAACCAGAATACGACCTGGAGCTGATAACATCATGTTCCTCCAATGTGTCAGTCGCGCACGATGCATCTGGCAAAAGGGTATACTACCTCACCCGTGACCCCACCACCCCCCTTGCACGGGCTGCGTGGGAGACAGCTAGACACACTCCAATCAACTCTTGGCTAGGCAATATCATCATGTATGCGCCCACCCTATGGGCAAGGATGATTCTGATGACTCACTTTTTCTCCATCCTTCTAGCTCAAGAGCAACTTGAAAAAGCCCTGGATTGTCAGATCTACGGGGCTTGCTACTCCATTGAGCCACTTGACCTACCTCAGATCATTGAACGACTCCATGGTCTTAGCGCATTTACAGTCCACAGTTACTCTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCACCCTTGCGAACCTGGAGACATCGGGCCAGAAGTGTCCGCGCTAAGCTACTGTCCCAGGGGGGGAGGGCCGCCACTTGTGGCAGATACCTGTTTAAGTGGGCAGTAAGGACCAAGCTTAAACTCACTCCAATCCCGGCCGCGTCCCAGCTGGACTTGTCTGGCTGGTTCGTCGCTGGTTACAGCGGGGGAGACATATATCACAGCGTGTCTCGTGCCCGACCCCGCTGGTTTCCGTTGTGCCTAGTCCTACTTTGTGTAGGGGTAGGCATTTACCTGCTCCCCAACCGATGAACGGGGAGCTAACCACTCCAGGCCTTAAGCCATTTCCTGTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTCTTTCCTTTCCTTCTTTTTTTCCTTTCTTTTTCCCTTCTTTAATGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCATGACTGCAGAGAGTGCTGATACTGGCCTCTCTGCAGAT CAaGT J4B/R1 (C):[SEQ ID NO: 10] GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTGTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAAGTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATfCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATGTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTGTGGATTCATCGAGTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTGGACCAGGACCTCGTCGGCTGGCAAGCGCCCCCCGGGGCGCGTTCCTTGACACCATGCACCTGCGGCAGCTCGGACCTTTACTTGGTCACGAGGCATGCCGATGTCATTCCGGTGCGCCGGCGGGGCGACAGCAGGGGGAGCCTACTCTCCCCCAGGCCCGTCTCGTACTTGAAGGGCTCTTCGGGCGGTCCACTGCTCTGCCCCTCGGGGCACGCTGTGGGCATCTTTCGGGCTGCCGTGTGCACCCGAGGGGTTGCGAAGGCGGTGGAGTTTGTACCCGTCGAGTCTATGGAAACCACTATGCGGTCCCCGGTCTTCACGGACAACTCGTCCCCTCCGGCCGTACCGCAGACATTCCAGGTGGCCCATCTACACGCCCCTACTGGTAGCGGCAAGAGCACTAAGGTGCCGGCTGCGTATGCAGCCCAAGGGTATAAGGTGCTTGTCCTGAACCCGTCCGTCGCCGCCACCCTAGGTTTCGGGGCGTATATGTCTAAGGCACATGGTATCGACCCTAACATCAGAACCGGGGTAAGGACCATCACCACGGGTGCCCCCATCACGTACTCCACCTATGGCAAGTTTCTTGCCGACGGTGGTTGCTCTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAAGTGACTCGACCACTATCCTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGACTCGTCGTGCTCGCCACCGCTACGCCTCCGGGATCGGTCACCGTGCCACATCCAAACATCGAGGAGGTGGCTCTGTCCAGCACTGGAGAAATCCCCTTTTATGGCAAAGCCATCCCCATCGAGACCATCAAGGGGGGGAGGCACCTCATTTTTCTGCCATTCCAAGAAGAAATGTGATGAGCTCGCCGCGAAGCTGTCCGGCCTCGGACTCAATGCTGTAGCATATTACCGGGGCCTTGATGTATCCGTCATACCAACTAGCGGAGACGTCATTGTCGTAGCAACGGACGCTCTAATGACGGGCTTTACCGGCGATTTCGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCCTGGACCCGACCTTCACCATTGAGACGACGACCGTGCCACAAGACGCGGTGTCACGCTCGCAGCGGCGAGGCAGGACTGGTAGGGGCAGGATGGGCATTTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCCTCGGTTCTGTGCGAGTGCTATGACGCGGGCTGTGCTTGGTACGAGCTCACGCCCGCCGAGACCTCAGTTAGGTTGCGGGCTTACGTAAACACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGAGCGTCTTTACAGGCCTCACCCACATAGACGCCCATTTCTTGTCCCAGACTAAGCAGGCAGGAGACAACTTCCCCTACCTGGTAGCATACCAGGCTACGGTGTGCGCCAGGGCTCAGGCTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTAAAGCCTACGCTGCACGGGCCAACGCCCCTGCTGTATAGGCTGGGAGCCGTTCAAAACGAGGTTACTACCACACACCCCATAACCAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACGAGCACCTGGGTGCTGGTAGGCGGAGTCCTAGCAGCTCTGGCCGCGTATTGCCTGACAACAGGCAGCGTGGTCATTGTGGGCAGGATCATCTTGTCCGGAAAGCCGGCCATCATTCCCGACAGGGAAGTCCTTTACCGGGAGTTCGATGAGATGGAAGAGTGCGCCTCACACCTCCCTTACATCGAACAGGGAATGCAGCTCGCCGAACAATTCAAACAGAAGGCAATCGGGTTGCTGCAAACAGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAATCCAAGTGGCGGACCCTCGAAGCCTTCTGGGCGAAGCATATGTGGAATTTCATCAGCGGGATACAATATTTAGCAGGCTTGTCCACTCTGCCTGGCAACCCCGCGATAGCATCACTGATGGCATTCACAGCCTCTATCACCAGCCCGCTCACCACCCAACATACCCTCCTGTTTAACATCCTGGGGGGATGGGTGGCCGCCCAACTTGCTCCTCCCAGCGCTGCTTCTGCTTTCGTAGGCGCCGGCATCGCTGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTTGTGGATATTTTGGCAGGTTATGGAGCAGGGGTGGCAGGCGCGCTCGTGGCCTTTAAGGTCATGAGCGGCGAGATGCCCTCCACCGAGGACCTGGTTAACCTACTCCCTGCTATCCTCTCCCCTGGCGCCCTAGTCGTCGGGGTCGTGTGCGCAGCGATACTGCGTCGGCACGTGGGCCCAGGGGAGGGGGCTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCCCACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCCTCTCTAGTCTTACCATCACTCAGCTGCTGAAGAGGCTTCACCAGTGGATCAACGAGGACTGCTCCACGCCATGCTCCGGCTCGTGGCTAAGAGATGTTTGGGATTGGATATGCACGGTGTTGACTGATTTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCGATTGCCGGGAGTCCCCTTCTTCTCATGTCAACGTGGGTACAAGGGAGTCTGGCGGGGCGACGGCATCATGCAAACCACCTGCCCATGTGGAGCACAGATCACCGGACATGTGAAAAACGGTTCCATGAGGATCGTGGGGCCTAGGACCTGTAGTAACACGTGGCATGGAACATTCCCCATTAACGCGTACACCACGGCCCCTGCACGCCCTCCCCGGCGCCAAATTATTCTAGGGCGCTGTGGCGGGTGGCTGCTGAGGAGTACGTGGAGGTTACGCGGGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCGTGTCAGGTTCCGGCCCCCGAATTCTTCACGGAGGTGGATGGAGTGCGGTTGCACAGGTACGCTCCGGCGTGCAAACCTCTTCTACGGGAGGACGTCACGTTCCAGGTCGGGCTCAACCAATACTTGGTCGGGTCGCAGCTCCCATGCGAGCCCGAACCGGACGTAACAGTGCTTACTTCCATGCTCACCGATCCCTCCCACATTACAGCAGAGACGGCTAAGCGTAGGCTGGCTAGAGGGTCTCCCCCCTCTTTAGCCAGCTCATCAGCTAtCCAGTTGTCTGCGCCTTCTTTGAAGGCGACATGCACTACCCACCATGACTCCCCGGACGCTGACGTCATCGAGGCCAACCTGTTGTGGCGGCAGGAGATGGGCGGAAACATCACTCGCGTGGAGTCAGAGAATAAGGTAGTAATTCTGGACTCTTTCGAACCGCTTCACGCGGAGGGGGATGAGAGGGAGATATCCGTCGCGGCGGAGATCCTGCGAAAATCCAGGAAGTTCCCCTCAGCGTTGCCCATATGGGCACGCCCGGACTACAATCCTCCACTGGTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCGGTGGTACACGGATGCCCATTGCCACCTACCAAGGCTCCTCCAATACCACCTCCACGGAGAAAGAGGACGGTTGTCCTGACAGAATCCAATGTGTCTTCTGCCTTGGCGGAGCTCGCCACTAAGACCTTCGGTAGCTCCGGATCGTCGGCCGTTGATAGCGGCACGGCGACCGCCCTTCCTGACCTGGCCTCCGACGACGGTGACAAAGGATCCGACGTTGAGTCGTACTCCTCCATGCCCCCCCTTGAAGGGGAGCCGGGGGACCCCGATCTCAGCGACGGGTCTTGGTCTACCGTGAGTGAGGAGGCTAGTGAGGATGTCGTCTGCTGCTCAATGTCCTATACGTGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAAGTAAGCTGCCCATCAACCCGTTGAGCAACTCTTTGCTGCGTCACCACAACATGGTCTACGCCACAACATCCCGCAGCGCAAGCCTCCGGCAGAAGAAGGTCACCTTTGACAGATTGCAAGTCCTGGATGATCATTACCGGGACGTACTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAGCTTCTATCTATAGAGGAGGCCTGCAAGCTGACGCCCCCACATTCGGCCAAATCCAAATTTGGCTATGGGGCAAAGGACGTCCGGAACCTATCCAGCAGGGCCGTTAACCACATCCGCTCCGTGTGGGAGGACTTGCTGGAAGACACTGAAACACCAATTGACACCACCATCATGGCAAAAAGTGAGGTTTTCTGCGTCCAACCAGAGAAGGGAGGCCGCAAGCCAGCTCGCCTTATCGTATTCCCAGACCTGGGAGTTCGTGTATGCGAGAAGATGGCCCTTTACGACGTGGTCTCCACCCTTCCTCAGGCCGTGATGGGCTCCTCATACGGATTTCAATACTCCCCCAAGCAGCGGGTCGAGTTCCTGGTGAATACCTGGAAATCAAAGAAATGCCCTATGGGCTTCTCATATGACACCCGCTGTTTTGACTCAACGGTCACTGAGAGTGACATTCGTGTTGAGGAGTCAATTTACCAATGTTGTGACTTGGCCCCCGAGGCCAGACAGGCCATAAGGTCGCTCACAGAGCGGCTTTACATCGGGGGTCCCCTGACTAACTCAAAAGGGCAGAACTGCGGTTATCGCCGGTGCCGCGCAAGTGGCGTGCTGACGACTAGCTGCGGTAATACCCTCACATGTTACTTGAAGGCCACTGCAGCCTGTCGAGCTGCAAAGCTCCAGGACTGCACGATGCTCGTGAACGGAGACGACCTTGTCGTTATCTGTGAAAGCGCGGGAACCCAGGAGGATGCGGCGGCCCTACGAGCCTTCACGGAGGCTATGACTAGGTATTCCGCCCCCCCCGGGGATCCGCCCCAACCAGAATACGACCTGGAGCTGATAACATCATGTTCCTCCAATGTGTCAGTCGCGCACGATGCATCTGGCAAAAGGGTATACTACCTCACCCGTGACCCCACCACCCCCCTTGCACGGGCTGCGTGGGAGACAGCTAGACACACTCCAATCAACTCTTGGCTAGGCAATATCATCATGTATGCGCCCACCCTATGGGCAAGGATGATTCTGATGACTCACTTTTTCTCCATCCTTCTAGCTCAAGAGCAACTTGAAAAAGCCCTGGATTGTCAGATGTACGCGGGGTTGCTACTCCATTGAGCCACTTGACCTACCTCAGATCATTGAACGACTCCATGGTCTTAGCGCATTTACACTCCACAGTTACTCTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCACCCTTGCGAACCTGGAGACATCGGGCCAGAAGTGTCCGCGCTAAGCTACTGTCCCAGGGGGGGAGGGCCGCCACTTGTGGCAGATACCTCTTTAACTGGGCAGTAAGGACCAAGCTTAAACTCACTCCAATCCCGGCCGCGTCCCAGCTGGACTTGTCTGGCTGGTTCGTCGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCTGGTTTCCGTTGTGCCTACTCCTACTTTCTGTAGGGGTAGGCATTTACCTGCTCCCCAACCGATGAACGGGGAGCTAACCACTCCAGGCCTTAAGCCATTTCCTGTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTCTTTCCTTTCCTTCTTTTTTTCCTTTCTTTTTCCCTTCTTTAATGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCtTGACTGCAGAGAGTGCTGATACTGGCCTCTCTGCAGATC AaGT J4Replicon: [SEQ ID NO: 11]GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGCACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCGTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGGTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTAGACCTGGACCTCGTCGGCTGGCAGGCGCCCCCCGGGGCGCGCTCCATGACACCATGCAGCTGTGGCAGCTCGGACCTTTACTTGGTCACGAGACATGCTGATGTCATTCCGGTGCGCCGGCGAGGCGACAGCAGGGGAAGTCTACTCTCCCCCAGGCCCGTCTCCTACCTGAAAGGCTCCTCGGGTGGTCCATTGCTTTGCCCTTCGGGGCACGTCGTGGGCGTCTTCCGGGCTGCTGTGTGCACCCGGGGGGTCGCGAAGGCGGTGGACTTCATACCCGTTGAGTCTATGGAAACTACCATGCGGTCTCCGGTGTTCACAGACAACTCAACCCCCCCGGCTGTACCGCAGACATTCCAAGTGGCACATCTGCACGCTCCTACTGGCAGCGGCAAGAGCACCAAAGTGCCGGCTGCGTATGCAGCCCAAGGGTACAAGGTGCTCGTCCTGAACCCGTCCGTTGCCGCCACCTTAGGGTTTGGGGCGTATATGTCCAAGGCACACGGTATCGACCCTAACATCAGAACTGGGGTAAGGACCATTACCACGGGCGGCTCCATTACGTACTCCACCTATGGCAAGTTCCTTGCCGACGGTGGCTGTTGTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAAGTGACTCGACTACCATCTTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGGCTCGTCGTGCTCGCCACCGCTACACCTCCGGGATCGGTTACCGTGCCACACCCCAATATCGAGGAAATAGGCCTGTCCAACAATGGAGAGATCCCCTTGTATGGCAAAGCCATCCCCATTGAGGCCATCAAGGGGGGGAGGCATCTCATTTTCTGCCATTCCAAGAAGAAATGTGACGAGCTCGCCGCAAAGCTGACAGGCCTCGGACTGAACGCTGTAGCATATTACCGGGGCCTTGATGTGTCCGTCATACCGCCTATCGGAGACGTCGTTGTCGTGGCAACAGACGCTCTAATGACGGGTTTCACCGGCGATTTTGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCTTGGATCCCACCTTCACCATTGAGACGACGACCGTGCCCCAAGACGCGGTGTCGCGCTCGCAACGGCGAGGTAGAACTGGCAGGGGTAGGAGTGGCATCTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCTTCGGTCCTGTGTGAGTGCTATGACGCGGGCTGTGCTTGGTATGAGCTCACGCCCGCTGAGACCTCGGTTAGGTTGCGGGCTTACCTAAATACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGAGCGTCTTCACAGGCCTCACCCACATAGATGCCCACTTCCTGTCCCAGACTAAACAGGCAGGAGACAACTTTCCTTACCTGGTGGCATATCAAGCTACAGTGTGCGCCAGGGCTCAAGCTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTGAAACCTACACTGCACGGGCCAACACCCCTGCTGTATAGGCTAGGAGCCGTCCAAAATGAGGTCATCCTCACACACCCCATAACTAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCAGTAGCACCTGGGTGGTGGTAGGCGGAGTCCTTGCAGCTTTGGCCGCATACTGCCTGACGACAGGCAGTGTGGTCATTGTGGGCAGGATCATCTTGTCCGGGAAGCCAGCTGTCGTTCCCGACAGGGAAGTCCTCTACCAGGAGTTCGATGAGATGGAAGAGTGTGCCTCACAACTTCCTTACATCGAGCAGGGAATGCAGCTCGCCGAGCAATTCAAGCAAAAGGCGCTCGGGTTGTTGCAAACGGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAGTCCAAGTGGCGAGCCCTTGAGACCTTCTGGGCGAAGCACATGTGGAATTTCATCAGCGGAATACAGTACCTAGCAGGCTTATCCACTCTGCCTGGAAACCCCGCGATAGCATCATTGATGGCATTTACAGCTTCTATCACTAGCCCGCTCACCACCCAAAACACCCTCCTGTTTAACATGTTGGGGGGATGGGTGGCTGCCCAACTCGCTCCTCCCAGCGCTGCGTCAGCTTTCGTGGGCGCCGGCATCGCCGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTCGTGGACATCTTGGCGGGCTATGGGGCAGGGGTAGCCGGCGCACTCGTGGCCTTTAAGGTCATGAGCGGCGAGGTGCCCTCCACCGAGGACCTGGTCAACTTACTCCCTGCCATCCTCTCTCCTGGTGCCCTGGTCGTCGGGGTCGTGTGCGCAGCAATACTGCGTCGGCACGTGGGCCCGGGAGAGGGGGCTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCCTACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCCTCTCTAGCCTTACCATCACTCAACTGGTGAAGCGGCTCCACCAGTGGATTAATGAGGACTGCTCTACGCCATGCTCCGGCTCGTGGCTAAGGGATGTTTGGGATTGGATATGCACGGTGTTGACTGACTTCAAGACCTGGCTCCAGTCCAAACTCCTGCCGCGGTTACCGGGAGTCCCTTTCCTGTCATGCCAACGCGGGTACAAGGGAGTCTGGCGGGGGGACGGCATCATGCAAACCACCTGCCCATGCGGAGCACAGATCGCCGGACATGTCAAAAACGGTTCCATGAGGATCGTAGGGCCTAGAACCTGCAGCAACACGTGGCACGGAACGTTCCCCATCAACGCATACACCACGGGACCTTGCACACCCTCCCCGGCGCCCAACTATTCCAGGGCGCTATGGCGGGTGGCTGCTGAGGAGTACGTGGAGGTTACGCGTGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCATGCCAGGTTCCGGCCCCCGAATTCTTCACGGAGGTGGATGGAGTGCGGTTGCACAGGTACGCTCCGGCGTGCAAACCTCTTCTACGGGAGGACGTCACGTTCCAGGTCGGGCTCAACCAATACTTGGTCGGGTCGCAGCTCCCATGCGAGCCCGAACCGGACGTAACAGTGCTTACTTCCATGCTCACCGATCCCTCCCACATTACAGCAGAGACGGCTAAGCGTAGGCTGGCTAGAGGGTCTCCCCCCTCTTTAGCCAGCTCATCAGCTAtCCAGTTGTCTGCGCCTTCTTTGAAGGCGACATGCACTACCCACCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCTTGTGGCGGCAGGAGATGGGCGGAAACATCACTCGCGTGGAGTCAGAGAATAAGGTAGTAATTCTGGACTCTTTCGAACCGCTTCACGCGGAGGGGGATGAGAGGGAGATATCCGTCGCGGCGGAGATCCTGCGAAAATCCAGGAAGTTCCCCTCAGCGTTGCCCATATGGGCACGCCCGGACTACAATCCTCCACTGCTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCGGTGGTACACGGATGCCCATTGCCACCTACCAAGGCTCCTCCAATACCACCTCCACGGAGAAAGAGGACGGTTGTCCTGACAGAATCCAATGTGTCTTCTGCCTTGGCGGAGCTCGCCACTAAGACCTTCGGTAGCTCCGGATCGTCGGCCGTTGATAGCGGCACGGCGACCGCCCTTCCTGACCTGGCCTCCGACGACGGTGACAAAGGATCCGACGTTGAGTCGTACTCCTCCATGCCCCCCCTTGAAGGGGAGCCGGGGGACCCCGATCTCAGCGACGGGTCTTGGTGTACCGTGAGTGAGGAGGCTAGTGAGGATGTCGTCTGCTGCTCAATGTCCTATACGTGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAAGTAAGCTGCCCATCAACCCGTTGAGCAACTTTTGCTGCGTCACCACAACATGGTCTACGCCACAACATCCCGCAGCGCAAGCCTCCGGCAGAAGAAGGTCACCTTTGACAGATTGCAAGTCCTGGATGATCATTACCGGGACGTACTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAGCTTCTATGTATAGAGGAGGCCTGCAAGCTGACGCCCCCACATTCGGCCAAATCCAAATTTGGCTATGGGGCAAAGGACGTCCGGAACCTATCCAGCAGGGCCGTTAACCACATCCGCTCCGTGTGGGAGGACTTGCTGGAAGACACTGAAACACCAATTGACACCACCATCATGGCAAAAAGTGAGGTTTTCTGCGTCCAACCAGAGAAGGGAGGCCGCAAGCCAGCTCGCCTTATCGTATCCCAGACCTGGGAGTTCGTGTATGCGAGAAGATGGCCCTTTACGACGTGGTCTCCACCCTTCCTCAGGCCGTGATGGGCTCCTCATACGGATTTCAATACTCCCCCAAGCAGCGGGTCGAGTTCCTGGTGAATACCTGGAAATCAAAGAAATGCCCTATGGGCTTCTCATATGACACCCGCTGTTTTGACTCAACGGTCACTGAGAGTGACATTCGTGTTGAGGAGTCAATTTACCAATGTTGTGACTTGGCCCCCGAGGCCAGACAGGCCATAAGGTCGCTCACAGAGCGGCTTTACATCGGGGGTCCCCTGACTAACTCAAAAGGGCAGAACTGCGGTTATCGCCGGTGCCGCGCAAGTGGCGTGCTGACGACTAGCTGCGGTAATACCCTCACATGTTACTTGAAGGCCACTGCAGCCTGTCGAGCTGCAAAGCTCCAGGACTGCACGATGCTCGTGAACGGAGACGACCTTGTCGTTATGTGTGAAAGCGCGGGAACCCAGGAGGATGCGGCGGCCCTACGAGCCTTCACGGAGGCTATGACTAGGTATTCCGCCCCCCCCGGGGATCCGCCCCAACCAGAATACGACCTGGAGCTGATAACATCATGTTCCTCCAATGTGTCAGTCGCGCACGATGCATCTGGCAAAAGGGTATACTACCTCACCCGTGACCCCACCACCCCCCTTGCACGGGCTGCGTGGGAGACAGCTAGACACACTCCAATCAACTCTTGGCTAGGCAATATCATCATGTATGCGCCCACCCTATGGGCAAGGATGATTCTGATGACTCACTTTTTCTCATCCTTCTAGCTCAAGAGCAACTTGAAAAAGCCCTGGATTGTCAGATCTACGGGGCTTGCTACTCCATTGAGCCACTTGACCTACCTCAGATCATTGAACGACTCCATGGTCTTAGCGCATTTACACTCCACAGTTACTCTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCACCCTTGCGAACCTGGAGACATCGGGCCAGAAGTGTCCGCGCTAAGCTACTGTCCCAGGGGGGGAGGGCCGCCACTTGTGGCAGATACCTCTTTAACTGGGCAGTAAGGACCAAGCTTAAAGTCACTCCAATCCCGGCCGCGTCCCAGCTGGACTTGTCTGGCTGGTTCGTCGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCTGGTTTCCGTTGTGCCTACTCCTACTTTCTGTAGGGGTAGGCATTTACCTGCTCCCCAACCGATGAACGGGGAGCTAACCACTCCAGGCCTTAAGCCATTTCCTGTTTTTTTTTTTTTTTTTTTTCCTTTCCTTCTTTTTTTCCTTTCTTTTTCCCTTCTTTAATGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCATGACTGCAGAGAGTGCTGATACTGGCCTCTCTGCAGAT CAaGT J4 replicon(c): [SEQ ID NO: 12]GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGGTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTGTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTAGACCTGGACCTCGTCGGCTGGCAGGCGCCCCCCGGGGCGCGCTCCATGACACCATGCAGCTGTGGCAGCTCGGACCTTTACTTGGTCACGAGACATGCTGATGTCATTCCGGTGCGCCGGCGAGGCGACAGCAGGGGAAGTCTACTCTCCCCCAGGCCCGTCTCCTACCTGAAAGGCTCCTCGGGTGGTCCATTGCTTTGCCCTTCGGGGCACGTCGTGGGCGTCTTCCGGGCTGGTGTGTGCACCCGGGGGGTCGCGAAGGCGGTGGACTTCATACCCGTTGAGTCTATGGAAACTACCATGCGGTCTCCGGTCTTCACAGACAACTCAACCCCCCCGGCTGTACCGCAGACATTCCAAGTGGCACATCTGCACGCTCCTACTGGCAGCGGCAAGAGCACCAAAGTGCCGGCTGCGTATGCAGCCCAAGGGTACAAGGTGCTCGTCCTGAACCCGTCCGTTGCCGCCACCTTAGGGTTTGGGGCGTATATGTCCAAGGCACACGGTATCGACCCTAACATCAGAACTGGGGTAAGGACCATTACCACGGGCGGCTCCATTACGTACTCCACCTATGGCAAGTTCCTTGCCGACGGTGGCTGTTCTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAACTGACTCGACTACCATCTTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGGCTCGTCGTGCTCGCCACCGCTACACCTCCGGGATCGGTTACCGTGCCACACCCCAATATCGAGGAAATAGGCCTGTCCAACAATGGAGAGATCCCCTTCTATGGCAAAGCCATCCCCATTGAGGCCATCAAGGGGGGGAGGCATCTCATTTTCTGCCATTCCAAGAAGAAATGTGACGAGCTCGCCGCAAAGCTGACAGGCCTCGGACTGAACGCTGTAGCATATTACCGGGGCCTTGATGTGTCCGTCATACCGCCTATCGGAGACGTCGTTGTCGTGGCAACAGACGCTCTAATGACGGGTTTCACCGGCGATTTTGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCTTGGATCCCACCTTCACCATTGAGACGACGACCGTGCCCCAAGACGCGGTGTCGCGCTCGCAACGGCGAGGTAGAACTGGCAGGGGTAGGAGTGGCATCTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCTTCGGTCCTGTGTGAGTGCTATGACGCGGGCTGTGCTTGGTATGAGCTCACGCCCGCTGAGACCTCGGTTAGGTTGCGGGCTTACCTAAATACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGAGCGTCTTCACAGGCCTCACCCACATAGATGCCCACTTCCTGTCCCAGACTAAACAGGCAGGAGACAACTTTCCTTACCTGGTGGCATATCAAGCTACAGTGTGCGCCAGGGCTCAAGCTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTGAAACCTACACTGCACGGGCCAACACCCCTGCTGTATAGGCTAGGAGCCGTCCAAAATGAGGTCATCCTCACACACCCCATAACTAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACTAGCACCTGGGTGCTGGTAGGCGGAGTCCTTGCAGCTTTGGCCGCATACTGCCTGACGACAGGCAGTGTGGTCATTGTGGGCAGGATCATCTTGTCCGGGAAGCCAGCTGTCGTTCCCGACAGGGAAGTCCTCTACCAGGAGTTCGATGAGATGGAAGAGTGTGCCTCACAACTTCCTTACATCGAGCAGGGAATGCAGCTCGCCGAGCAATTCAAGCAAAAGGCGCTCGGGTTGTTGCAAACGGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAGTCCAAGTGGCGAGCCCTTGAGACCTTCTGGGCGAAGCACATGTGGAATTTCATCAGCGGAATACAGTACCTAGCAGGCTTATCCACTCTGCCTGGAAACCCCGCGATAGCATCATTGATGGCATTTACAGCTTCTATCACTAGCCCGCTCACCACCCAAAACACCCTCCTGTTTAACATCTTGGGGGGATGGGTGGCTGCCCAACTCGCTCCTCCCAGCGCTGCGTCAGCTTTCGTGGGCGCCGGCATCGCCGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTCGTGGACATCTTGGCGGGCTATGGGGCAGGGGTAGCCGGCGCACTCGTGGCCTTTAAGGTCATGAGCGGCGAGGTGCCCTCCACCGAGGACCTGGTCAACTTACTCCCTGCCATCCTCTCTCCTGGTGCCCTGGTCGTCGGGGTCGTGTGCGCAGCAATACTGCGTCGGCACGTGGGCCCGGGAGAGGGGGCTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCGTACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCGTCTGTAGCCTTACCATCACTCAACTGCTGAAGCGGCTCCACCAGTGGATTAATGAGGACTGCTCTACGCCATGCTCCGGCTCGTGGCTAAGGGATGTTTGGGATTGGATATGCACGGTGTTGACTGACTTCAAGACCTGGCTCCAGTCCAAACTCCTGCCGCGGTTACCGGGAGTCCCTTTCGTGTCATGCCAACGCGGGTACAAGGGAGTCTGGCGGGGGGACGGCATCATGCAAACCACCTGCCCATGCGGAGCACAGATCGCCGGACATGTCAAAAACGGTTCCATGAGGATCGTAGGGCCTAGAACCTGCAGCAACACGTGGCACGGAACGTTCCCCATCAACGCATACACCACGGGACCTTGCACACCCTCCCCGGCGCCCAACTATTCCAGGGCGCTATGGCGGGTGGCTGCTGAGGAGTACGTGGAGGTTACGCGTGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCATGCCAGGTTCCGGCCCCCGAATTCTTCACGGAGGTGGATGGAGTGCGGTTGCACAGGTACGCTCCGGCGTGCAAACCTCTTCTACGGGAGGACGTCACGTTCCAGGTCGGGCTCAACCAATACTTGGTCGGGTCGCAGCTCCCATGCGAGCCCGAACCGGACGTAACAGTGCTTACTTCCATGCTCACCGATCCCTCCCACATTACAGCAGAGACGGCTAAGCGTAGGCTGGCTAGAGGGTCTCCCCCCTCTTTAGCCAGCTCATCAGCTAtCCAGTTGTCTGCGCCTTCTTTGAAGGCGACATGCACTACCCACCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCTTGTGGCGGCAGGAGATGGGCGGAAACATCACTCGCGTGGAGTCAGAGAATAAGGTAGTAATTCTGGACTCTTTCGAACCGCTTCACGCGGAGGGGGATGAGAGGGAGATATCCGTCGCGGCGGAGATCCTGCGAAAATCCAGGAAGTTCCCCTCAGCGTTGCCCATATGGGCACGCCCGGACTACAATCCTCCACTGCTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCGGTGGTACACGGATGCCCATTGCCACCTACCAAGGCTCCTCCAATACCACCTCCACGGAGAAAGAGGACGGTTGTCCTGACAGAATCCAATGTGTCTTCTGCCTTGGCGGAGCTCGCCACTAAGACCTTCGGTAGCTCCGGATCGTCGGCCGTTGATAGCGGCACGGCGACCGCCCTTCCTGACCTGGCCTCCGACGACGGTGACAAAGGATCCGACGTTGAGTCGTACTCCTCCATGCCCCCCCTTGAAGGGGAGCCGGGGGACCCCGATGTCAGCGACGGGTCTTGGTCTACCGTGAGTGAGGAGGCTAGTGAGGATGTCGTCTGCTGCTCAATGTCGTATACGTGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAAGTAAGCTGCCCATCAACCCGTTGAGCAACTCTTTGCTGCGTCACCACAACATGGTCTACGCCACAACATCCCGCAGCGCAAGCCTCCGGCAGAAGAAGGTCACCTTTGACAGATTGCAAGTCCTGGATGATCATTACCGGGACGTACTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAGCTTCTATCTATAGAGGAGGCCTGCAAGCTGACGCCCCCACATTCGGCCAAATCCAAATTTGGCTATGGGGCAAAGGACGTCCGGAACGTATCCAGCAGGGCCGTTAACCACATCCGCTCCGTGTGGGAGGACTTGCTGGAAGACACTGAAACACCAATTGACACCACCATCATGGCAAAAAGTGAGGTTTTCTGCGTCCAACCAGAGAAGGGAGGCCGCAAGCCAGCTCGCCTTATCGTATTCCCAGACCTGGGAGTTCGTGTATGCGAGAAGATGGCCCTTTACGACGTGGTCTCCACCCTTCCTCAGGCCGTGATGGGCTCCTCATACGGATTTCAATACTCCCCCAAGCAGCGGGTCGAGTTCCTGGTGAATACCTGGAAATCAAAGAAATGCCCTATGGGCTTCTCATATGACACCCGCTGTTTTGACTCAACGGTCACTGAGAGTGACATTCGTGTTGAGGAGTCAATTTACCAATGTTGTGACTTGGCCCCCGAGGCCAGACAGGCCATAAGGTCGCTCACAGAGCGGCTTTACATCGGGGGTCCCCTGAGTAACTCAAAAGGGCAGAACTGCGGTTATCGCCGGTGCCGCGCAAGTGGCGTGCTGACGACTAGCTCGGGTAATACCCTCACATGTTACTTGAAGGCCACTGCAGCCTGTCGAGCTGCAAAGCTCCAGGACTGCACGATGCTCGTGAACGGAGACGACCTTGTCGTTATCTGTGAAAGCGCGGGAACCCAGGAGGATGCGGCGGCCCTACGAGCCTTCACGGAGGCTATGACTAGGTATTCCGCCCCCCCCGGGGATCCGCCCCAACCAGAATACGACCTGGAGCTGATAACATCATGTTCCTCCAATGTGTCAGTCGCGCACGATGCATCTGGCAAAAGGGTATACTACCTCACCCGTGACCCCACCACCCCCCTTGCACGGGCTGCGTGGGAGACAGCTAGACACACTCCAATCAACTCTTGGCTAGGCAATATCATCATGTATGCGCCCACCCTATGGGCAAGGATGATTCTGATGACTCACTTTTTCTCCATCCTTCTAGCTCAAGAGCAACTTGAAAAAGCCCTGGATTGTCAGATCTACGGGGCTTGCTACTCCATTGAGCCACTTGACCTACCTCAGATCATTGAACGACTCCATGGTCTTAGCGCATTTACACTCCACAGTTACTCTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCACCCTTGCGAACCTGGAGACATCGGGCCAGAAGTGTCCGCGCTAAGCTACTGTCCCAGGGGGGGAGGGCCGCCACTTGTGGCAGATACCTCTTTAACTGGGCAGTAAGGACCAAGCTTAAACTCACTCCAATCCCGGCCGCGTCCCAGCTGGACTTGTCTGGCTGGTTCGTCGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCTGGTTTCCGTTGTGCCTACTCCTACTTTCTGTAGGGGTAGGCATTTACCTGCTCCCCAACCGATGAACGGGGAGCTAACCACTCCAGGCCTTAAGCCATTTCCTGTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTTTTTTTTTTTCTTTCCTTTCCTTCTTTTTTTCCTTTCTTTTTCCCTTCTTTAATGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCtTGACTGCAGAGAGTGCTGATAGTGGCCTCTCTGCAGATC AaGT BB7/J4NS5B:[SEQ ID NO: 13] GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCGTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGCTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGGTGTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATGTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCCTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTGTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTGTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCGTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTGGACCAGGACCTCGTCGGCTGGCAAGCGCCCCCCGGGGCGCGTTCCTTGACACCATGCACCTGCGGCAGCTCGGACCTTTACTTGGTCACGAGGCATGCCGATGTCATTCCGGTGCGCCGGCGGGGCGACAGCAGGGGGAGCCTACTCTCCCCCAGGCCCGTCTCCTACTTGAAGGGCTCTTCGGGCGGTCCACTGCTCTGCCCCTCGGGGCACGCTGTGGGCATCTTTCGGGCTGCCGTGTGCACCCGAGGGGTTGCGAAGGCGGTGGACTTTGTACCCGTCGAGTCTATGGAAACCACTATGCGGTCCCCGGTCTTCACGGACAACTCGTCCCCTCCGGCCGTACCGCAGACATTCCAGGTGGCCCATCTACACGCCCCTACTGGTAGCGGCAAGAGCACTAAGGTGCCGGCTGCGTATGCAGCCCAAGGGTATAAGGTGCTTGTCCTGAACCCGTCCGTCGCCGCCACCCTAGGTTTCGGGGCGTATATGTCTAAGGCACATGGTATCGACCCTAACATCAGAACCGGGGTAAGGACCATCACCACGGGTGCCCCCATCACGTACTCCACCTATGGCAAGTTTCTTGCCGACGGTGGTTGCTCTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAACTGACTCGACCACTATCCTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGACTCGTCGTGCTCGCCACCGCTACGCCTCCGGGATCGGTCACCGTGCCACATCCAAACATCGAGGAGGTGGCTCTGTCCAGCACTGGAGAAATCCCCTTTTATGGCAAAGCCATCCCCATCGAGACCATCAAGGGGGGGAGGCACCTCATTTTCTGCCATTCCAAGAAGAAATGTGATGAGCTCGCCGCGAAGCTGTCCGGCCTCGGACTCAATGCTGTAGCATATTACCGGGGCCTTGATGTATCCGTCATACCAACTAGCGGAGACGTCATTGTCGTAGCAACGGACGCTCTAATGACGGGCTTTACCGGCGATTTCGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCCTGGACCCGACCTTCACCATTGAGACGACGACCGTGCCACAAGACGCGGTGTCACGCTCGCAGCGGCGAGGCAGGACTGGTAGGGGCAGGATGGGCATTTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCCTCGGTTCTGTGCGAGTGCTATGACGCGGGCTGTGCTTGGTACGAGCTCACGCCCGCCGAGACCTCAGTTAGGTTGCGGGCTTACCTAAACACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGAGCGTCTTTACAGGCCTCACCCACATAGACGCCCATTTCTTGTCCCAGACTAAGCAGGCAGGAGACAACTTCCCCTACCTGGTAGCATACCAGGCTACGGTGTGCGCCAGGGCTCAGGCTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTAAAGCCTACGCTGCACGGGCCAACGCCCCTGCTGTATAGGCTGGGAGCCGTTCAAAACGAGGTTACTACCACACACCCCATAACCAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACGAGCACCTGGGTGCTGGTAGGCGGAGTCCTAGCAGCTCTGGCCGCGTATTGCCTGACAACAGGCAGCGTGGTCATTGTGGGCAGGATCATCTTGTCCGGAAAGCCGGCCATCATTCCCGACAGGGAAGTCCTTTACCGGGAGTTCGATGAGATGGAAGAGTGCGCCTCACACCTCCCTTACATCGAACAGGGAATGCAGCTCGCCGAACAATTCAAACAGAAGGCAATCGGGTTGCTGCAAACAGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAATCCAAGTGGCGGACCCTCGAAGCCTTCTGGGCGAAGCATATGTGGAATTTCATCAGCGGGATACAATATTTAGCAGGCTTGTCCACTCTGCCTGGCAACCCCGCGATAGCATCACTGATGGCATTCACAGCCTCTATCACCAGCCCGCTCACCACCCAACATACCCTCCTGTTTAACATCCTGGGGGGATGGGTGGCCGCCCAACTTGCTCCTCCCAGCGCTGCTTCTGCTTTCGTAGGCGCCGGCATCGCTGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTTGTGGATATTTTGGCAGGTTATGGAGCAGGGGTGGCAGGCGCGCTCGTGGCCTTTAAGGTCATGAGCGGCGAGATGCCCTCCACCGAGGACCTGGTTAACCTACTCCCTGCTATCCTCTCCCCTGGCGCCCTAGTCGTCGGGGTCGTGTGCGCAGCGATACTGCGTCGGCACGTGGGCCCAGGGGAGGGGGCTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCCCACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCCTCTCTAGTCTTACCATCACTCAGCTGCTGAAGAGGCTTCACCAGTGGATCAACGAGGACTGCTCCACGCCATGCTCCGGCTCGTGGCTAAGAGATGTTTGGGATTGGATATGCACGGTGTTGACTGATTTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCGATTGCCGGGAGTCCCCTTCTTCTCATGTCAACGTGGGTACAAGGGAGTCTGGCGGGGCGACGGCATCATGCAAACCACCTGCCCATGTGGAGCACAGATCACCGGACATGTGAAAAACGGTTCCATGAGGATCGTGGGGCCTAGGACCTGTAGTAACACGTGGCATGGAACATTCCCCATTAACGCGTACACCACGGGCCCCTGCACGCCCTCCCCGGCGCCAAATTATTCTAGGGCGCTGTGGCGGGTGGCTGCTGAGGAGTACGTGGAGGTTACGCGGGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCGTGTCAGGTTCCGGCCCCCGAATTCTTCACAGAAGTGGATGGGGTGCGGTTGCACAGGTACGCTCCAGCGTGCAAACCCCTCCTACGGGAGGAGGTCACATTCCTGGTCGGGCTCAATCAATACCTGGTTGGGTCACAGCTCCCATGCGAGCCCGAACCGGACGTAGCAGTGCTCACTTCCATGCTCACCGACCCCTCCCACATTACGGCGGAGACGGCTAAGCGTAGGCTGGCCAGGGGATCTCCCCCCTCCTTGGCCAGCTCATCAGCTATCCAGCTGTCTGCGCCTTCCTTGAAGGCAACATGCACTACCCGTCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCCTGTGGCGGCAGGAGATGGGCGGGAACATCACCCGCGTGGAGTCAGAAAATAAGGTAGTAATTTTGGACTCTTTCGAGCCGCTCCAAGCGGAGGAGGATGAGAGGGAAGTATCCGTTCCGGCGGAGATCCTGCGGAGGTCCAGGAAATTCCCTCGAGCGATGCCCATATGGGCACGCCCGGATTACAACCCTCCACTGTTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCAGTGGTACACGGGTGTCCATTGCCGCCTGCCAAGGCCCCTCCGATACCACCTCCACGGAGGAAGAGGACGGTTGTCCTGTCAGAATCTACCGTGTCTTCTGCCTTGGCGGAGCTCGCCACAAAGACCTTCGGCAGCTCCGAATCGTCGGCCGTCGACAGCGGCACGGCAACGGCCTCTCCTGACCAGCCCTCCGACGACGGCGACGCGGGATCCGACGTTGAGTCGTACTCCTCCATGCCCCCCCTTGAGGGGGAGCCGGGGGATCCCGATCTCAGCGACGGGTCTTGGTCTACCGTAAGCGAGGAGGCTAGTGAGGACGTCGTCTGCTGCTCGATGTCCTACACATGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAAGTAAGCTGCCCATCAACCCGTTGAGCAACTCTTTGCTGCGTCACCACAACATGGTCTACGCCACAACATCCCGCAGCGCAAGCCTCCGGCAGAAGAAGGTCACCTTTGACAGATTGCAAGTCCTGGATGATCATTACCGGGACGTACTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAGCTTCTATCTATAGAGGAGGCCTGCAAGCTGACGCCCCCACATTCGGCCAAATCCAAATTTGGCTATGGGGCAAAGGACGTCCGGAACCTATCCAGCAGGGCCGTTAACCACATCCGCTCCGTGTGGGAGGACTTGCTGGAAAGACACTGAAACACCAATTGACACCACCATCATGGCAAAAAGTGAGGTTTTCTGCGTCCAACCAGAGAAGGGAGGCCGCGCAAGCCAGCTCGCCTTATCGTATTCCCAGACCTGGGAGTTCGTGTATGCGAGAAGATGGCCCTTTACGACGTGGTCTCCACCCTTCCTCAGGCCGTGATGGGCTCCTCATACGGATTTCAATACTCCCCCAAGCAGCGGGTCGAGTTCCTGGTGAATACCTGGAAATCAAAGAAATGCCCTATGGGCTTCTCATATGACACCCGCTGTTTTGACTCAACGGTCACTGAGAGTGACATTCGTGTTGAGGAGTCAATTTACCAATGTTGTGACTTGGCCCCCGAGGCCAGACAGGCCATAAGGTCGCTCACAGAGCGGCTTTACATCGGGGGTCCCCTGACTAACTCAAAAGGGCAGAACTGCGGTTATCGCCGGTGCCGCGCAAGTGGCGTGCTGACGACTAGCTGCGGTAATACCCTCACATGTTACTTGAAGGCCACTGCAGCCTGTCGAGCTGCAAAGCTCCAGGACTGCACGATGCTCGTGAACGGAGACGACCTTGTCGTTATGTGTGAAAGCGCGGGAACCCAGGAGGATGCGGCGGCCCTACGAGCCTTCACGGAGGCTATGACTAGGTATTCCGCCCCCCCCGGGGATCCGCCCCAACCAGAATACGACCTGGAGCTGATAACATCATGTTCCTCCAATGTGTCAGTCGCGCACGATGCATCTGGCAAAAGGGTATACTACCTCACCCGTGACCCCACCACCCCCCTTGCACGGGCTGCGTGGGAGACAGCTAGACACACTCCAATCAACTCTTGGCTAGGCAATATCATCATGTATGCGCCCACCCTATGGGCAAGGATGATTCTGATGACTCACTTTTTCTCCATCCTTCTAGCTCAAGAGCAACTTGAAAAAGCCCTGGATTGTCAGATCTACGGGGCTTGCTACTCCATTGAGCCACTTGACCTACCTCAGATCATTGAACGACTCCATGGTCTTAGCGCATTTACACTCCACAGTTACTCTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCACCCTTGCGAACCTGGAGACATCGGGCCAGAAGTGTCCGCGCTAAGCTACTGTCCCAGGGGGGGAGGGCCGCCACTTGTGGCAGATACCTCTTTAACTGGGCAGTAAGGACCAAGCTTAAACTCACTCCAATCCCGGCCGCGTCCCAGTGGACTTGTCTGGCTGGTTCGTCGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCTGGTTCCGTTGTGCCTACTCCTACTTTCTGTAGGGGTAGGCATTTACCTGCTCCCCAACCGATGAACGGGtAcgTAAACACTCCAGGCCAATAGGCCATCCTGTTTTTTTCCCTTTTTTTTTTTCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTCCTTTTTTTTTCCTCTTTTTTTCCTTTTCTTTCCTTTGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCTTGAGTGCAGAGAGTGCTGATACTGGCCT CTCTGCAGATCAAGTpBB7-SN: [SEQ ID NO: 14] BB7-SN:GCCAGCCCCCGATTGGGGGCGACACTCCACCATAGATCACTCCCCTGTGAGGAACTACTGTCTTCACGCAGAAAGCGTCTAGCCATGGCGTTAGTATGAGTGTCGTGCAGCCTCCAGGACCCCCCCTCCCGGGAGAGCCATAGTGGTCTGCGGAACCGGTGAGTACACCGGAATTGCCAGGACGACCGGGTCCTTTCTTGGATCAACCCGCTCAATGCCTGGAGATTTGGGCGTGCCCCCGCGAGACTGCTAGCCGAGTAGTGTTGGGTCGCGAAAGGCCTTGTGGTACTGCCTGATAGGGTGGTTGCGAGTGCCCCGGGAGGTCTCGTAGACCGTGCACCATGAGCACGAATCCTAAACCTCAAAGAAAAACCAAAGGGCGCGCCATGATTGAACAAGATGGATTGCACGCAGGTTCTCCGGCCGCTTGGGTGGAGAGGCTATTCGGCTATGACTGGGCACAACAGACAATCGGCTGCTCTGATGCCGCCGTGTTCCGGCTGTCAGCGCAGGGGCGCCCGGTTCTTTTTGTCAAGACCGACCTGTCCGGTGCCCTGAATGAACTGCAGGACGAGGCAGCGCGGCTATCGTGGCTGGCCACGACGGGCGTTCCTTTGCGCAGCTGTGCTCGACGTTGTCACTGAAGCGGGAAGGGACTGGCTGCTATTGGGCGAAGTGCCGGGGCAGGATCTCCTGTCATCTCACCTTGCTCCTGCCGAGAAAGTATCCATCATGGCTGATGCAATGCGGCGGCTGCATACGCTTGATCCGGCTACCTGCCCATTCGACCACCAAGCGAAACATCGCATCGAGCGAGCACGTACTCGGATGGAAGCCGGTCTTGTCGATCAGGATGATCTGGACGAAGAGCATCAGGGGCTCGCGCCAGCCGAACTGTTCGCCAGGCTCAAGGCGCGCATGCCCGACGGCGAGGATCTCGTCGTGACCCATGGCGATGCCTGCTTGCCGAATATCATGGTGGAAAATGGCCGCTTTTCTGGATTCATCGACTGTGGCCGGCTGGGTGTGGCGGACCGCTATCAGGACATAGCGTTGGCTACCCGTGATATTGCTGAAGAGCTTGGCGGCGAATGGGCTGACCGCTTCCTCGTGCTTTACGGTATCGCCGCTCCCGATTCGCAGCGCATCGCCTTCTATCGCGTTCTTGACGAGTTCTTCTGAGTTTAAACAGACCACAACGGTTTCCCTCTAGCGGGATCAATTCCGCCCCTCTCCCTCCCCCCCCCCTAACGTTACTGGCCGAAGCCGCTTGGAATAAGGCCGGTGTGCGTTTGTCTATATGTTATTTTCCACCATATTGCCGTCTTTTGGCAATGTGAGGGCCCGGAAACCTGGCCCTGTCTTCTTGACGAGCATTCCTAGGGGTCTTTCCCCTCTCGCCAAAGGAATGCAAGGTCTGTTGAATGTCGTGAAGGAAGCAGTTCCTCTGGAAGCTTCTTGAAGACAAACAACGTCTGTAGCGACCCTTTGCAGGCAGCGGAACCCCCCACCTGGCGACAGGTGCCTCTGCGGCCAAAAGCCACGTGTATAAGATACACCTGCAAAGGCGGCACAACCCCAGTGCCACGTTGTGAGTTGGATAGTTGTGGAAAGAGTCAAATGGCTCTCCTCAAGCGTATTCAACAAGGGGCTGAAGGATGCCCAGAAGGTACCCCATTGTATGGGATCTGATCTGGGGCCTCGGTGCACATGCTTTACATGTGTTTAGTCGAGGTTAAAAAACGTCTAGGCCCCCCGAACCACGGGGACGTGGTTTTCCTTTGAAAAACACGATAATACCATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCAGTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATGTACACCAATGTGGACCAGGACCTCGTCGGCTGGCAAGCGCCCCCCGGGGCGCGTTCCTTGACACCATGCACCTGCGGCAGCTCGGACCTTTACTTGGTCACGAGGCATGCCGATGTCATTCCGGTGCGCCGGCGGGGCGACAGCAGGGGGAGCCTACTCTCCCCCAGGCCCGTCTCCTACTTGAAGGGCTCTTCGGGCGGTCCACTGCTCTGCCCCTCGGGGCACGCTGTGGGCATCTTTCGGGCTGCCGTGTGCACCCGAGGGGTTGCGAAGGCGGTGGACTTTGTACCCGTCGAGTCTATGGAAACCACTATGCGGTCCCCGGTCTTCACGGACAACTCGTCCCCTCCGGCCGTACCGCAGACATTCCAGGTGGCCCATCTACACGCCCCTACTGGTAGCGGCAAGAGCACTAAGGTGCCGGCTGCGTATGCAGCCCAAGGGTATAAGGTGCTTGTCCTGAACCCGTCCGTCGCCGCCACCCTAGGTTTCGGGGCGTATATGTCTAAGGCACATGGTATCGACCCTAACATCAGAACCGGGGTAAGGACCATCACCACGGGTGCCCCCATCACGTACTCCACCTATGGCAAGTTTCTTGCCGACGGTGGTTGCTCTGGGGGCGCCTATGACATCATAATATGTGATGAGTGCCACTCAACTGACTCGACCACTATCCTGGGCATCGGCACAGTCCTGGACCAAGCGGAGACGGCTGGAGCGCGACTCGTCGTGCTCGCCACCGCTACGCCTCCGGGATCGGTCACCGTGCCACATCCAAACATCGAGGAGGTGGCTCTGTCCAGCACTGGAGAAATCCCCTTTTATGGCAAAGCCATCCCCATCGAGACCATCAAGGGGGGGAGGCACCTCATTTTCTGCCATTCCAAGAAGAAATGTGATGAGCTCGCCGCGAAGCTGTCCGGCCTCGGACTCAATGCTGTAGCATATTACCGGGGCCTTGATGTATCCGTCATACCAACTAGCGGAGACGTCATTGTCGTAGCAACGGACGCTCTAATGACGGGCTTTACCGGCGATTTCGACTCAGTGATCGACTGCAATACATGTGTCACCCAGACAGTCGACTTCAGCCTGGACCCGACCTTCACCATTGAGACGACGACCGTGCCACAAGACGCGGTGTCACGCTCGCAGCGGCGAGGCAGGACTGGTAGGGGCAGGATGGGCATTTACAGGTTTGTGACTCCAGGAGAACGGCCCTCGGGCATGTTCGATTCCTCGGTTCTGTGCGAGTGCTATGACGCGGGCTGTGCTTGGTACGAGCTCACGCCCGCCGAGACCTCAGTTAGGTTGCGGGCTTACCTAAACACACCAGGGTTGCCCGTCTGCCAGGACCATCTGGAGTTCTGGGAGAGCGTCTTTACAGGCCTCACCCACATAGACGCCCATTTCTTGTCCCAGACTAAGCAGGCAGGAGACAACTTCCCCTACCTGGTAGCATACCAGGCTACGGTGTGCGCCAGGGCTCAGGGTCCACCTCCATCGTGGGACCAAATGTGGAAGTGTCTCATACGGCTAAAGCCTACGCTGCACGGGCCAACGCCCCTGCTGTATAGGCTGGGAGCCGTTCAAAACGAGGTTACTACCACACACCCCATAACCAAATACATCATGGCATGCATGTCGGCTGACCTGGAGGTCGTCACGAGCACCTGGGTGCTGGTAGGCGGAGTCCTAGCAGCTCTGGCCGCGTATTGCCTGACAACAGGCAGCGTGGTCATTGTGGGCAGGATCATCTTGTCCGGAAAGCCGGCCATCATTCCCGACAGGGAAGTCCTTTACCGGGAGTTCGATGAGATGGAAGAGTGCGCCTCACACCTCCCTTACATCGAACAGGGAATGCAGCTCGCCGAACAATTCAAACAGAAGGCAATCGGGTTGCTGCAAACAGCCACCAAGCAAGCGGAGGCTGCTGCTCCCGTGGTGGAATCCAAGTGGCGGACCCTCGAAGCCTTCTGGGCGAAGCATATGTGGAATTTCATCAGCGGGATACAATATTTAGCAGGCTTGTCCACTCTGCCTGGCAACCCCGCGATAGCATCACTGATGGCATTCACAGCCTCTATCACCAGCCCGCTCACCACCCAACATACCCTCCTGTTTAACATCCTGGGGGGATGGGTGGCCGCCCAACTTGCTCCTCCCAGCGCTGCTTCTGCTTTCGTAGGCGCCGGCATCGCTGGAGCGGCTGTTGGCAGCATAGGCCTTGGGAAGGTGCTTGTGGATATTTTGGCAGGTTATGGAGCAGGGGTGGCAGGCGCGCTCGTGGCCTTTAAGGTCATGAGCGGCGAGATGCCCTCCACCGAGGACCTGGTTAACCTACTCCCTGCTATCCTCTCCCCTGGCGCCCTAGTCGTCGGGGTCGTGTGCGCAGCGATACTGCGTCGGCACGTGGGCCCAGGGGAGGGGGCTGTGCAGTGGATGAACCGGCTGATAGCGTTCGCTTCGCGGGGTAACCACGTCTCCCCCACGCACTATGTGCCTGAGAGCGACGCTGCAGCACGTGTCACTCAGATCCTCTCTAGTCTTACCATCACTCAGCTGCTGAAGAGGCTTCACCAGTGGATCAACGAGGACTGCTCCACGCCATGCTCCGGCTCGTGGCTAAGAGATGTTTGGGATTGGATATGCACGGTGTTGACTGATTTCAAGACCTGGCTCCAGTCCAAGCTCCTGCCGCGATTGCCGGGAGTCCCCTTCTTCTCATGTCAACGTGGGTACAAGGGAGTCTGGCGGGGCGACGGCATCATGCAAACCACCTGCCCATGTGGAGCACAGATCACCGGACATGTGAAAAACGGTTCCATGAGGATCGTGGGGCCTAGGACCTGTAGTAACACGTGGCATGGAACATTCCCCATTAACGCGTACACCACGGGCCCCTGCACGCCCTCCCCGGCGCCAAATTATTCTAGGGCGCTGTGGCGGGTGGCTGCTGAGGAGTACGTGGAGGTTACGCGGGTGGGGGATTTCCACTACGTGACGGGCATGACCACTGACAACGTAAAGTGCCCGTGTCAGGTTCCGGCCCCCGAATTCTTCACAGAAGTGGATGGGGTGCGGTTGCACAGGTACGCTCCAGCGTGCAAACCCCTCCTACGGGAGGAGGTCACATTCCTGGTCGGGCTCAATCAATACCTGGTTGGGTCACAGCTCCCATGCGAGCCCGAACCGGACGTAGCAGTGCTCACTTCCATGCTCACCGACCCCTCCCACATTACGGCGGAGACGGCTAAGCGTAGGCTGGCCAGGGGATCTCCCCCGTCCTTGGCCAGCTCATCAGCTATCCAGCTGTCTGCGCCTTCCTTGAAGGCAACATGCACTACCCGTCATGACTCCCCGGACGCTGACCTCATCGAGGCCAACCTCCTGTGGCGGCAGGAGATGGGCGGGAACATCACCCGCGTGGAGTCAGAAAATAAGGTAGTAATTTTGGACTCTTTCGAGCCGCTCCAAGCGGAGGAGGATGAGAGGGAAGTATCCGTTCCGGCGGAGATCCTGCGGAGGTCCAGGAAATTCCCTCGAGCGATGCCCATATGGGCACGCCCGGATTACAACCCTCCACTGTTAGAGTCCTGGAAGGACCCGGACTACGTCCCTCCAGTGGTACACGGGTGTCCATTGCCGCCTGCCAAGGCCCCTCCGATACCACCTCCACGGAGGAAGAGGACGGTTGTCCTGTCAGAATCTACCGTGTCTTCTGCCTTGGCGGAGCTCGCCACAAAGACCTTCGGCAGCTCCGAATCGTCGGCCGTCGACAGCGGCACGGCAACGGCCTCTCCTGACCAGCCCTCCGACGACGGCGACGCGGGATCCGACGTTGAGTCGTACTCCTCCATGCCCCCCCTTGAGGGGGAGCCGGGGGATCCCGATCTCAGCGACGGGTCTTGGTCTACCGTAAGCGAGGAGGCTAGTGAGGACGTCGTCTGCTGCTCGATGTCGTACACATGGACAGGCGCCCTGATCACGCCATGCGCTGCGGAGGAAACCAAGCTGCCCATCAATGCACTGAGCAACTCTTTGCTCCGTCACCACAACTTGGTCTATGGTACAACATCTCGCAGCGCAAGCCTGCGGCAGAAGAAGGTCACCTTTGACAGACTGCAGGTCCTGGACGACCACTACCGGGACGTGCTCAAGGAGATGAAGGCGAAGGCGTCCACAGTTAAGGCTAAACTTCTATCCGTGGAGGAAGCCTGTAAGCTGACGCCCCCACATTCGGCCAGATCTAAATTTGGCTATGGGGCAAAGGACGTCCGGAACCTATCCAGCAAGGCCGTTAACCACATCCGCTCCGTGTGGAAGGACTTGCTGGAAGACACTGAGACACCAATTGACACCACCATCATGGCAAAAAATGAGGTTTTCTGCGTCCAACCAGAGAAGGGGGGCCGCAAGCCAGCTCGCCTTATCGTATTCCCAGATTTGGGGGTTCGTGTGTGCGAGAAAATGGCCCTTTACGATGTGGTCTCCACCCTCCCTCAGGCCGTGATGGGCTCTTCATACGGATTCCAATACTCTCCTGGACAGCGGGTCGAGTTCCTGGTGAATGCCTGGAAAGCGAAGAAATGCCCTATGGGCTTCGCATATGACACCCGCTGTTTTGACTCAACGGTCACTGAGAATGACATCCGTGTTGAGGAGTCAATCTACCAATGTTGTGACTTGGCCCCCGAAGCCAGACAGGCCATAAGGTCGCTCACAGAGCGGCTTTACATCGGGGGCCCCCTGACTAATTCTAAAGGGCAGAACTGCGGCTATCGCCGGTGCCGCGCGAGCGGTGTACTGACGACCAGCTGCGGTAATACCCTCACATGTTACTTGAAGGCCGCTGCGGCCTGTCGAGCTGCGAAGCTCCAGGACTGCACGATGCTCGTATGCGGAGACGACCTTGTCGTTATCTGTGAAAGCGCGGGgACCCAAGAGGACGAGGCGAGCCTACGGGCCTTCACGGAGGCTATGACTAGATACTCTGCCCCCCCTGGGGACCCGCCCAAACCAGAATACGACTTGGAGTTGATAACATCATGCTCCTCCAATGTGTCAGTCGCGCACGATGCATCTGGCAAAAGGGTGTACTATCTCACCCGTGACCCCACCACCCCCCTTGCGCGGGCTGCGTGGGAGACAGCTAGACACACTCCAGTCAATTCCTGGCTAGGCAACATCATCATGTATGCGCCCACCTTGTGGGCAAGGATGATCCTGATGACTCATTTCTTCTCCATCCTTCTAGCTCAGGAACAACTTGAAAAAGCCCTAGATTGTCAGATCTACGGGGCCTGTTACTCCATTGAGCCACTTGACCTACCTCAGATCATTCAACGACTCCATGGCCTTAGCGCATTTTCACTCCATAGTTACTCTCCAGGTGAGATCAATAGGGTGGCTTCATGCCTCAGGAAACTTGGGGTACCGCCCTTGCGAGTCTGGAGACATCGGGCCAGAAGTGTCCGCGCTAGGCTACTGTCCCAGGGGGGGAGGGCTGCCACTTGTGGCAAGTACCTCTTCAACTGGGCAGTAAGGACCAAGCTCAAACTCACTCCAATCCCGGCTGCGTCCCAGTTGGATTTATCCAGCTGGTTCGTTGCTGGTTACAGCGGGGGAGACATATATCACAGCCTGTCTCGTGCCCGACCCCGCTGGTTCATGTGGTGCCTACTCCTACTTTCTGTAGGGGTAGGCATCTATCTAGTCCCCAACCGATGAACGGGtACgTAAACACTCCAGGCCAATAGGCCATCCTGTTTTTTTCCCTTTTTTTTTTTCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTCTCCTTTTTTTTTCCTCTTTTTTTCCTTTTCTTTCCTTTGGTGGCTCCATCTTAGCCCTAGTCACGGCTAGCTGTGAAAGGTCCGTGAGCCGCTTGACTGCAGAGAGTGCTGATACTGGCCT CTGTGCAGATCAAGT(C) Primers

DNA primer sequences used in making the chimeric replicon constructs.Primers of the invention were derived from plasmids also described inthe disclosure. BG1000: CAT CCA GAT GTA CAC CAA TGT GGA C [SEQ ID NO:31] BG1001: CAT CGC CCG AAT TCT TCA CAG AAT TG [SEQ ID NO: 32] BG1002:CAA TTC TGT GAA GAA TTC GGG CGA TG [SEQ ID NO: 33] BG1003: GTA ACA CCAATT GAC ACT ACC ATC [SEQ ID NO: 34] BG1004: GAT GGT AGT GTC TAT TGG TGTTAC [SEQ ID NO: 35] RB8000: GCA CTA GTA CTT GAT CTG CAG AGA [SEQ ID NO:36] GGC CAG TAT CAG CAC TCT CTG CAG TCA AGC GG J4-9841T: CTT TAG CCA GCTCAT CAG CTA TCC [SEQ ID NO: 37] AGT TGT CTG CGC CTT C J49841TR: GAA GGCGCA GAC AAC TGG ATA GCT [SEQ ID NO: 38] GAT GAG CTG GCT AAA C 1aS9484IR: GAG ATG GAG CGG ACA GCT GGA TAG [SEQ ID NO: 39] CCG AGG AGC TGG CCATAG AAG 1aS9484I: CTT CTA TGG CCA GCT CCT CGG CTA [SEQ ID NO: 40] TCCAGC TGT CCG CTC CAT CTC rb6000: CGT CTG CTG CTC GAT GTC CTA C [SEQ IDNO: 41] RB7801 3′CTC CCC CAA CCG ATG AAC GGG TAC [SEQ ID NQ: 42] GTA AACACT CCA GGC CAA TAG 1A 10501 CCT GGA CAG GCG CAC TGA TCA CC [SEQ ID NO:43] J4-10861 GAG GAC TTG CTG GAA GAC ACT G [SEQ ID NO: 44] BB7980 CAGGAG TAC TTG ATC TGC AGA GAG GC [SEQ ID NQ: 45] BG1005: GCA CTA GTA CTTGAT CTG CAG AGA [SEQ ID NO: 46] GGC RB7801 5′CTA TTG GCC TGG AGT GTT TACGTA [SEQ ID NO: 47] CCC GTT CAT CGG TTG GGG GAG Ralf Neo 5′TCA AGA CCGACC TGT CCG GTG CCC [SEQ ID NO: 48] Ralf Neo 3′CTT GAG CCT GGC GAA CAGTTC GGC [SEQ ID NO: 49 GAPDH for ACC ACA GTC CAT GCC ATC AC [SEQ ID NO:50] GAPDH rev TCC ACC ACC CTG TTG CTG TA [SEQ ID NO: 51] Neo^(R) fwd CCGGCT ACC TGC CCA TTC [SEQ ID NO: 52] Neo^(R) rev CCA GAT CAT CCG ATC GACAAG [SEQ ID NO: 53] 5′FAM- ACA TCG CAT CGA GCG AGC ACG TAC- [SEQ ID NO:54] TAMRA 3′

The following is a list of documents related to the above disclosure andparticularly to the experimental procedures and discussions.

-   Lohmann V., Korner, F. Koch, J., Herian U. Theilmann, L., and    Bartenschlager, R. Replication of subgenomic hepatitis C virus RNAs    in a hepatoma cell line. Science 285:110, 1999-   Blight, K. J. Kolykhalov, A. A and Rice C. M. Efficient initiation    of HCV RNA replication in cell culture. Science 290:1972-4, 2000-   Guo J. Bichko, V. and Seeger C 2001 Effect of alpha interferon on    the hepatitis C virus replicon. J Virol. Septenber 2001;    75(18):8516-23.-   Yanagi, M, St claire, M., Shapiro, M, Emerson, S. U. Purcell, R. H.    and Bukh, J. 1998, Transcripts of a chimeric cDNA clone of hepatitis    C virus genotype 1b are infectious in vivo. Virology, 244:161-72.-   Yanagi, M, Purcell, R. H., M, Emerson, S. U. and Bukh, J. 1997    Transcripts from a single full-length cDNA clone of hepatitis C    virus are infectious when directly transfected into the liver of a    chimpanzee. Proc Natl Acad Sci USA. 94:8738-43.-   Yanagi, M, St claire, M., Emerson, S. U., Purcell, R. H., and    Bukh, J. 1999. In vivo analysis of the 3′ untranslated region of the    hepatitis C virus after in vivo mutagenesis of an infectious cDNA    clone. PNAS 96:2291-2295-   Simmonds, P. et al. 1994 A proposed system for the nomenclature of    hepatitis C viral genotypes. Hepatology 19:1321-1324.-   Lindsay, K. L. 1997. Therapy of hepatitis C: overview. Hepatology.    1997 71S-77S.-   Choo, Q. L. Kuo, G., Weiner, A. J., Overby, L. R. Bradley, D. W. and    Houghton, M. 1989 Isolation of a cDNA clone derived from a    blood-borne non-A, non-B viral hepatitis genome. Science,    244:359-362.-   Miller, R. H. and Purcell, R. H, 1990 Hepatitis C virus shares amino    acid sequence similarity with pestiviruses and flaviviruses as well    as members of two plant virus supergroups. Proc Natl Acad Sci USA.    87:2057-61.-   Kuo, G. et al., 1989 An assay for circulating antibodies to a major    etiologic virus of human non-A, non-B hepatitis. Science. Apr. 26,    1989; 244(4902):362-4.-   Wang, C. and Siddiqui, A. 1995. Structure and function of the    hepatitis C virus internal ribosome entry site. Curr Top Microbiol    Immunol. 1995; 203:99-115.-   Kolykhalov A. A. Feinstone, S. M. Rice C. M. 1996; Identification of    a highly conserved sequence element at the 3′ terminus of hepatitis    C virus genome RNA. J Virol. 1996 70:3363-71.-   Tanaka, T. Kato, N., Cho, M. J., and Shimotohno, K. 1995; A. novel    sequence found at the 3′ terminus of hepatitis C virus genome.    Biochem. Biophys. Res. Commun. 215;744-749.-   Tanaka, T., Kato, N., Cho, M. J., Sugiyama, K., and Shimotohno, K.    1996; Structure of the 3′ terminus of the hepatitis C virus genome.    J Virol. 70:3307-12.-   Yamada, N., K. Tanihara, A. Takada, T. Yorihuzi, M. Tsutsumi, H.    Shimomura, T. Tsuji, T. Date 1996. Genetic Organization and    Diversity of the 3′ Noncoding Region of the Hepatitis C Virus    Genome, Virology, 223: 255-261.

1. A sub-genomic viral replicon comprising: (a) a nucleic acid constructencoding chimeric HCV nonstructural protein, and (b) an NS5B polymerasegene.
 2. A replicon of claim 1 wherein the NS5B polymerase gene is froman HCV strain and linked in cis to a 3′UTR from said strain.
 3. Areplicon of claim 1 wherein the chimeric nonstructural proteins comprisea protein selected from the group consisting of NS3, NS4A, NS4B, NS5A,and NS5B.
 4. A replicon of claim 1 comprising an NS3 nucleotide sequencethat encodes the first 75 contiguous N-terminal amino acids of the NS3of genotype 1b, of a BB7 strain.
 5. A replicon of claim 1 wherein theNS3 N-terminal nucleotide sequence comprises [SEQ ID NO: 1]ATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATG.


6. A replicon of claim 4 wherein said NS3 N-terminal nucleotide sequencereplaces the N-terminal first 225 nucleotides of an NS3 from any of sixmajor HCV genotypes selected from the group consisting of HCV genotype1, 2, 3, 4, 5 and
 6. 7. A replicon of claim 6 wherein the NS3 is fromHCV genotype 1a.
 8. A replicon of claim 7 wherein the HCV genotype 1a isfrom an H77 strain.
 9. A sub-genomic viral replicon comprising: (a) anucleic acid construct encoding chimeric HCV nonstructural proteins, and(b) at least the C-terminal end of a strain specific NS5B polymerasegene linked in cis to a 3′LTR sequence from said strain.
 10. A repliconof claim 9 wherein the chimeric nonstructural proteins comprise aprotein selected from the group consisting of NS3, NS4A, NS4B, NS5A, andNS5B.
 11. A replicon of claim 9 comprising an NS3 nucleotide sequencethat encodes about the first 75 contiguous N-terminal amino acids of theNS3 of genotype 1b, of a BB7 strain.
 12. A replicon of claim 9 whereinthe NS3 N-terminal nucleotide sequence comprises [SEQ ID No: 1]ATGGCGCCTATTACGGCCTACTCCCAACAGACGCGAGGCCTACTTGGCTGCATCATCACTAGCCTCACAGGCCGGGACAGGAACCAGGTCGAGGGGGAGGTCCAAGTGGTCTCCACCGCAACACAATCTTTTCCTGGCGACCTGCGTCAATGGCGTGTGTTGGACTGTCTATCATGGTGCCGGCTCAAAGACCCTTGCCGGCCCAAAGGGCCCAATCACCCAAATG.


13. A replicon of claim 11 wherein said NS3 N-terminal nucleotidesequence replaces the N-terminal first 225 nucleotides of an NS3 fromany of six major HCV genotypes selected from the group consisting of HCVgenotype 1, 2, 3, 4, 5, and
 6. 14. A replicon of claim 13 wherein theNS3 is from HCV genotype 1b.
 15. A replicon of claim 14 wherein the NS3,genotype 1b, is from a J4 strain.
 16. A sub-genomic viral repliconcomprising SEQ ID NO:2, SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:8.
 17. Amethod of generating a cell comprising a replicating chimericsub-genomic viral replicon, said method comprising introducing saidchimeric replicon into a cell.
 18. A cell comprising a replicatingchimeric sub-genomic viral replicon.
 19. The cell of claim 18 whereinthe HCV sub-genomic replicon comprises all of the non-structural HCVgenes and none of the structural HCV genes.
 20. A method of screeningfor compounds that modulate viral replication comprising the steps of:a) administering a test compound to a cell of claim 18, and b)determining whether said test compound modulates the replication of saidchimeric replicon.
 21. A method of screening for compounds that inhibitviral replication comprising the steps of a) administering a testcompound to a cell of claim 18, and b) determining whether said testcompound inhibits the replication of said chimeric sub-genomic viralreplicon.